US11814386B2 - Fused pyrrolines which act as ubiquitin-specific protease 30 (USP30) inhibitors - Google Patents

Fused pyrrolines which act as ubiquitin-specific protease 30 (USP30) inhibitors Download PDF

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US11814386B2
US11814386B2 US18/048,079 US202218048079A US11814386B2 US 11814386 B2 US11814386 B2 US 11814386B2 US 202218048079 A US202218048079 A US 202218048079A US 11814386 B2 US11814386 B2 US 11814386B2
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cyano
azabicyclo
carboxamide
heptan
pyrazole
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Alex J. Buckmelter
Justin Andrew Caravella
Hongbin Li
Matthew W. Martin
Steven Mischke
David James Richard
Angela V. WEST
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Forma Therapeutics Inc
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/18—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Definitions

  • Ubiquitin-Specific Protease 30 USP30
  • novel compounds and methods for inhibiting USP30 are useful in the field of medicine including the development of new therapies (e.g., for the treatment of conditions related to the therapeutic inhibition of USP30 such as Parkinson's Disease (PD)).
  • PD Parkinson's Disease
  • the ubiquitination system is a highly regulated process which affects a wide variety of cellular activities and physiological processes. Ubiquitination is a reversible process, facilitated by a group of proteins known as deubiquitinating enzymes (DUBs), which deconjugate ubiquitin (Ub) from the substrate. DUBs are encoded by approximately 100 human genes and are divided into six families, with the largest family being the ubiquitin-specific proteases (USPs) with more than 50 members.
  • DUBs deubiquitinating enzymes
  • USPs ubiquitin-specific proteases
  • Ubiquitination regulates mitochondrial dynamics and biogenesis, affecting the abundance and function of these organelles. Mitochondria serve many functions to maintain cell health in mammals, including generating ATP. As mitochondria age they become damaged, losing their metabolic functionality, and begin releasing pro-apoptotic proteins. Mitochondria self-regulate their quality via the mechanism of mitophagy, which is the selective removal of damaged mitochondria from the cell. Ubiquitination of mitochondrial proteins is believed to contribute to mitochondrial dynamics in mammalian cells, possibly by “flagging” those proteins for inactivation. Ubiquitin-Specific Protease 30 (USP30) is embedded in the outer membrane of mitochondria, where it participates in the maintenance of mitochondrial morphology. It is believed that over-expression of USP30 can lead to a decrease in mitophagy.
  • Inactivating mutations in PINK1 and Parkin can impair mitophagy and result in accumulation of damaged mitochondria and neuronal toxicity, which has been implicated in Parkinson's Disease.
  • USP30 opposes the ligase activity of Parkin and is a negative regulator of mitophagy. USP30 inhibition is expected to promote mitophagy and restore mitochondrial health.
  • the disclosure provides compounds useful for inhibiting USP30, including USP30 Inhibitor Compounds as defined herein.
  • the disclosure provides a compound of formula (I):
  • R a , R b , R c , R d , R e , R f , R g , and R h are defined as follows:
  • the disclosure provides a compound of formula (I-C):
  • R 2 , R 5 , n, p, R a , R b , R c , R d , R e , R f , R g , and R h are all as defined for formula (I) above and described in classes and subclasses herein for formula (I), both singly and in combination.
  • a USP30 Inhibitor Compound is a compound selected from the group consisting of:
  • R 2 , R 5 , n, and p are as defined with respect to formula (I) herein, or a pharmaceutically acceptable salt thereof, having an IC 50 value of about ⁇ 1 ⁇ M (and preferably ⁇ 0.5 ⁇ M or ⁇ 0.1 ⁇ M) and >0.001 ⁇ M as measured in a Ubiquitin-Rhodamine 110 Assay as described in Example 1.
  • compounds of formula (I-C) are provided where R 2 and R 5 are both hydrogen.
  • a USP30 Inhibitor Compound is a compound of the chemical formula:
  • R 2 , R 5 , n, and p are as defined with respect to formula (I) herein, or a pharmaceutically acceptable salt thereof, having an IC 50 value of about ⁇ 1 ⁇ M (and preferably ⁇ 0.5 ⁇ M or ⁇ 0.1 ⁇ M) and >0.001 ⁇ M as measured in a Ubiquitin-Rhodamine 110 Assay as described in Example 1.
  • a compound is any compound selected from the compounds listed in Table 1 herein.
  • the present disclosure relates to compounds of formula (I), as defined herein, pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising same, and medical uses involving same.
  • the compounds of formula (I) are USP30 Inhibitor Compounds.
  • the compounds of formula (I) are useful, for example, as analytical tools and/or control compounds in biological assays (e.g., compounds of any of the following aspects and embodiments that are not USP30 Inhibitor Compounds).
  • USP30 Inhibitor Compounds are useful in the development of new therapies for Parkinson's disease (PD), and in methods of treating diseases or conditions by inhibiting USP30 (such as PD).
  • Parkin (E3 ubiquitin ligase) and PINK1 (kinase) are key regulators of mitophagy.
  • PINK1 localization to the mitochondrial outer membrane (MOM) and exposure to the cytosol is limited by rapid import to the mitochondrial inner membrane (MIM).
  • PINK1 is processed by several proteases, such as presenilin associated rhomboid-like protease (PARL), to yield a truncated version of PINK1 which is subsequently degraded by the proteasome (Meissner et al., Autophagy. 2015, 11(9), 1484-1498).
  • PARL presenilin associated rhomboid-like protease
  • PINK1 Upon mitochondrial depolarization or dysfunction, PINK1 accumulates in the MOM, recruiting and activating Parkin via PINK1-dependent phosphorylation of both ubiquitin and Parkin. Consequently, activated Parkin ubiquitinates MOM proteins like TOMM20 to trigger mitophagy (Pickrell et al., Neuron.
  • USP30 is embedded in the MOM with its catalytic DUB domain oriented towards the cytosol and has been shown to antagonize Parkin-mediated ubiquitination of common substrates, consequently opposing Parkin-mediated mitophagy. Genetic silencing of USP30 results in increased ubiquitination of several Parkin substrates followed by increased mitophagy. In model organisms, USP30 depletion is able to rescue mitophagy defects caused by pathogenic Parkin mutations, as well as restore mitochondria morphology and function, and dopamine levels. (Nakamura, et al., Mol Biol Cell. 2008, 19(5), 1903-1911; Bingol, et al., Nature 2014, 510(7505):370-5). Therefore, inhibition of USP30 with a compound disclosed herein could present a novel treatment paradigm for PD by promoting mitochondrial turnover.
  • alkyl means a substituted or unsubstituted hydrocarbon chain that is completely saturated, including straight-chain alkyl groups and branched-chain alkyl groups, and that has a single point of attachment to the rest of the molecule.
  • a straight chain or branched chain alkyl has about 1-20 carbon atoms in its backbone (e.g., C 1 -C 20 for straight chain, C 2 -C 20 for branched chain), and alternatively, about 1-10.
  • an alkyl has about 1-8 carbon atoms.
  • an alkyl has about 1-6 carbon atoms.
  • an alkyl has about 1-5 carbon atoms.
  • an alkyl has about 1-4 carbon atoms.
  • an alkyl has about 1-3 carbon atoms.
  • an alkyl has about 1-2 carbon atoms.
  • alkylene refers to a bivalent alkyl group.
  • exemplary alkylenes include —CH 2 —, —CH 2 CH 2 —, —CH(CH 3 )—, —CH 2 CH(CH 3 )—, —CH(CH 3 )CH 3 )—, etc.
  • an “alkylene chain” is a polymethylene group, i.e., —(CH 2 ) n —, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3.
  • a substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent.
  • alkenyl refers to an alkyl group, as defined herein, having one or more double bonds.
  • alkenylene refers to a bivalent alkenyl group.
  • a substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent.
  • alkynyl refers to an alkyl group, as defined herein, having one or more triple bonds.
  • aryl refers to ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members.
  • aryl may be used interchangeably with the term “aryl ring.”
  • aryl refers to an aromatic ring system and exemplary groups include phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents.
  • aryl is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.
  • arylene refers to a bivalent aryl group (e.g., phenylene).
  • cycloalkyl refers to a cyclic alkyl group (e.g., a monocyclic alkyl group or a bicyclic alkyl group). In some embodiments, “cycloalkyl” refers to a monocyclic C 3 -C 8 cycloalkyl group. In some embodiments, “cycloalkyl” refers to a monocyclic C 3 -C 6 cycloalkyl group.
  • heteroaryl refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 ⁇ electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms wherein the term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.
  • heteroaryl groups include thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl.
  • heteroaryl also includes groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring.
  • Examplary groups include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one.
  • heteroaryl group may be mono- or bicyclic.
  • heteroaryl may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted.
  • heteroarylene refers to a bivalent heteroaryl group.
  • heterocycloalkyl refers to a stable 3- to 7-membered monocyclic or 7- to 10-membered bicyclic cyclic moiety that is saturated and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms independently selected from nitrogen, oxygen, and sulfur, including any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.
  • the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or + NR (as in N-substituted pyrrolidinyl).
  • a heterocycloalkyl ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.
  • heterocycloalkyl radicals examples include tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl.
  • heterocycloalkyl also includes groups in which a heterocycloalkyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the heterocycloalkyl ring.
  • a “USP30 Inhibitor Compound” refers to a compound having an IC 50 of about 1 micromolar or less (i.e., an IC 50 value of ⁇ 1 ⁇ M and >0.001 ⁇ M) in the Ubiquitin-Rhodamine 110 Assay for USP30 as described in Example 1 herein.
  • a USP30 Inhibitor can be a compound of formula (I) having an IC 50 value of ⁇ 0.5 ⁇ M and >0.001 ⁇ M when tested in the Biochemical Assay of Example 1.
  • a USP30 Inhibitor is a compound of formula (I) having an IC 50 value of ⁇ 0.1 ⁇ M and >0.001 ⁇ M when tested in the Biochemical Assay of Example 1.
  • the term “pharmaceutically acceptable salt” refers to salts of such compounds that are appropriate for use in pharmaceutical contexts, i.e., salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977).
  • the enantiomer having the absolute stereochemistry suggested by the stereochemical descriptors is present in substantially enantiomerically pure form. In other embodiments, the enantiomer having the absolute stereochemistry opposite to that suggested by the stereochemical descriptors is present in substantially enantiomerically pure form.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this disclosure.
  • reference to a compound of formula (I) is intended to also include formulas I-1, I-2, I-3, I-4, I-A, I-A-1, I-A-2, I-A-3, I-A-4, I-B, I-B-1, I-B-2, I-B-3, I-B-4, I-C, I-C-1, I-C-2, I-C-3, I-C-4, I-C-a, I-C-b, I-C-c, I-C-d, I-C-e, I-C-f, I-D, I-E, I-E-1, I-E-2, I-E-3, I-E-4, I-F-1, I-F-2, I-G-1, I-G-2, I-H-1, I-H-2, I-J-1, I-J-2, I-K-1, I-K-2, I-L-1, I-L-2, I-M, I-M-1, I-M-2, I-M, I-M-1, I-M-2, I
  • the disclosure relates to a compound of formula (I):
  • the present disclosure provides compounds, or pharmaceutically acceptable salts thereof, of formula (I-1):
  • the present disclosure provides compounds, or pharmaceutically acceptable salts thereof, of formula (I-2):
  • the present disclosure provides compounds, or pharmaceutically acceptable salts thereof, of formula (I-3):
  • the present disclosure provides compounds, or pharmaceutically acceptable salts thereof, of formula (I-4):
  • the disclosure relates to a compound of formula (I-A):
  • the present disclosure provides compounds, or pharmaceutically acceptable salts thereof, of formula (I-A-1):
  • the present disclosure provides compounds, or pharmaceutically acceptable salts thereof, of formula (I-A-2):
  • the present disclosure provides compounds, or pharmaceutically acceptable salts thereof, of formula (I-A-3):
  • the present disclosure provides compounds, or pharmaceutically acceptable salts thereof, of formula (I-A-4):
  • the disclosure relates to a compound of formula (I-B):
  • the present disclosure provides compounds, or pharmaceutically acceptable salts thereof, of formula (I-B-1):
  • the present disclosure provides compounds, or pharmaceutically acceptable salts thereof, of formula (I-B-2):
  • the present disclosure provides compounds, or pharmaceutically acceptable salts thereof, of formula (I-B-3):
  • the present disclosure provides compounds, or pharmaceutically acceptable salts thereof, of formula (I-B-4):
  • the disclosure relates to a compound of formula (I-C):
  • R 2 , R 3 , n, p, R a , R b , R c , R d , R e , R f , R g and R h are all as defined for formula (I) above and described in classes and subclasses herein for formula (I), both singly and in combination.
  • the present disclosure provides compounds, or pharmaceutically acceptable salts thereof, of formula (I-C-1):
  • the present disclosure provides compounds, or pharmaceutically acceptable salts thereof, of formula (I-C-2):
  • the present disclosure provides compounds, or pharmaceutically acceptable salts thereof, of formula (I-C-3):
  • the present disclosure provides compounds, or pharmaceutically acceptable salts thereof, of formula (I-C-4):
  • the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (I-C-a):
  • R 2 , R 5 , n, and p are all as defined for formula (I-C) above and described in classes and subclasses herein for formula (I-C), both singly and in combination.
  • the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (I-C-b):
  • R 2 , R 5 , n, and p are all as defined for formula (I-C) above and described in classes and subclasses herein for formula (I-C), both singly and in combination.
  • the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (I-C-c):
  • R 2 , R 5 , n, and p are all as defined for formula (I-C) above and described in classes and subclasses herein for formula (I-C), both singly and in combination.
  • the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (I-C-d):
  • R 2 , R 5 , n, and p are all as defined for formula (I-C) above and described in classes and subclasses herein for formula (I-C), both singly and in combination.
  • the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (I-C-e):
  • R 2 , R 5 , n, and p are all as defined for formula (I-C) above and described in classes and subclasses herein for formula (I-C), both singly and in combination.
  • the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (I-C-f):
  • R 2 , R 5 , n, and p are all as defined for formula (I-C) above and described in classes and subclasses herein for formula (I-C), both singly and in combination.
  • the disclosure relates to a compound of formula (I-D):
  • R a , R b , R c , R d , R e , R f , R g and R h are all as defined for formula (I) above and described in classes and subclasses herein for formula (I), both singly and in combination.
  • the disclosure relates to a compound of formula (I-E):
  • R a , R b , R c , R d , R e , R f , and R g are all as defined for formula (I) above and described in classes and subclasses herein for formula (I), both singly and in combination.
  • the present disclosure provides compounds, or pharmaceutically acceptable salts thereof, of formula (I-E-1):
  • the compound of formula (I-E-1) has the absolute stereochemistry of the first eluting isomer when a racemic mixture of the compound of formula (I-E-1) is separated by the procedure described in Example 3, Step 6. In some embodiments, the compound of formula (I-E-1) has the absolute stereochemistry of the second eluting isomer when a racemic mixture of the compound of formula (I-E-1) is separated by the procedure described in Example 3, Step 6.
  • the compound of formula (I-E-1) is:
  • the compound of formula (I-E-1) is:
  • the present disclosure provides compounds, or pharmaceutically acceptable salts thereof, of formula (I-E-2):
  • the compound of formula (I-E-2) has the absolute stereochemistry of the first eluting isomer when a racemic mixture of the compound of formula (I-E-2) is separated by the procedure described in Example 4, Step 6. In some embodiments, the compound of formula (I-E-2) has the absolute stereochemistry of the second eluting isomer when a racemic mixture of the compound of formula (I-E-2) is separated by the procedure described in Example 4, Step 6.
  • the compound of formula (I-E-2) is:
  • the compound of formula (I-E-2) is:
  • the present disclosure provides compounds, or pharmaceutically acceptable salts thereof, of formula (I-E-3):
  • the compound of formula (I-E-3) has the absolute stereochemistry of the first eluting isomer when a racemic mixture of the compound of formula (I-E-3) is separated by the procedure described in Example 2, Step 7. In some embodiments, the compound of formula (I-E-3) has the absolute stereochemistry of the second eluting isomer when a racemic mixture of the compound of formula (I-E-3) is separated by the procedure described in Example 2, Step 7.
  • the compound of formula (I-E-3) is:
  • the compound of formula (I-E-3) is:
  • the present disclosure provides compounds, or pharmaceutically acceptable salts thereof, of formula (I-E-4):
  • the compound of formula (I-E-4) has the absolute stereochemistry of the first eluting isomer when a racemic mixture of the compound of formula (I-E-4) is separated by the procedure described in Example 2, Step 7. In some embodiments, the compound of formula (I-E-4) has the absolute stereochemistry of the second eluting isomer when a racemic mixture of the compound of formula (I-E-4) is separated by the procedure described in Example 2, Step 7.
  • the compound of formula (I-E-4) is:
  • the compound of formula (I-E-4) is:
  • the disclosure relates to a compound of formula (I-F-1) or (I-F-2):
  • X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , L, and M are all as defined for formula (I-A) above and described in classes and subclasses herein for formula (I-A), both singly and in combination.
  • the compounds of formula (I-F-1) and (I-F-2) are present in a racemic mixture. In other embodiments, the compound of formula (I-F-1) or (J-F-2) is present in substantially enantiomerically pure form.
  • the compounds of formula (I-F-1) and (I-F-2) can be separated from one another by chiral HPLC, such as by the procedure described in Example 2, Step 7 or Example 3, Step 6.
  • the disclosure relates to a compound of formula (I-G-1) or (I-G-2):
  • X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , L, and M are all as defined for formula (I-A) above and described in classes and subclasses herein for formula (I-A), both singly and in combination.
  • the compounds of formula (I-G-1) and (I-G-2) are present in a racemic mixture. In other embodiments, the compound of formula (I-G-1) or (I-G-2) is present in substantially enantiomerically pure form.
  • the compounds of formula (I-G-1) and (I-G-2) can be separated from one another by chiral HPLC, such as by the procedure described in Example 2, Step 7, or Example 4, Step 6.
  • the disclosure relates to a compound of formula (I-H-1) or (I-H-2):
  • X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , L, and M are all as defined for formula (I-A) above and described in classes and subclasses herein for formula (I-A), both singly and in combination.
  • the compounds of formula (I-H-1) and (I-H-2) are present in a racemic mixture. In other embodiments, the compound of formula (I-H-1) or (I-H-2) is present in substantially enantiomerically pure form.
  • the compounds of formula (I-H-1) and (I-H-2) can be separated from one another by chiral HPLC, such as by the procedure described in Example 2, Step 7.
  • the disclosure relates to a compound of formula (I-J-1) or (I-J-2):
  • X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , L, and M are all as defined for formula (I-A) above and described in classes and subclasses herein for formula (I-A), both singly and in combination.
  • the compounds of formula (I-J-1) and (I-J-2) are present in a racemic mixture. In other embodiments, the compound of formula (I-J-1) or (I-J-2) is present in substantially enantiomerically pure form.
  • the compounds of formula (I-J-1) and (I-J-2) can be separated from one another by chiral HPLC, such as by the procedure described in Example 2, Step 7.
  • the present disclosure provides compounds, or pharmaceutically acceptable salts thereof, of formula (I-K-1) or (I-K-2):
  • M, L, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 are all as defined for formula (I-A) above and described in classes and subclasses herein for formula (I-A), both singly and in combination.
  • the present disclosure provides compounds, or pharmaceutically acceptable salts thereof, of formula (I-L-1) or (I-L-2):
  • M, L, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 are all as defined for formula (I-A) above and described in classes and subclasses herein for formula (I-A), both singly and in combination.
  • the present disclosure provides compounds, or pharmaceutically acceptable salts thereof, of formula (I-M):
  • M, L, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , R a , R b , R c , R d , R e , R f , R g , and R h are all as defined for formula (I) and (I-A) above and described in classes and subclasses herein for formula (I) and (I-A), both singly and in combination.
  • the present disclosure provides compounds, or pharmaceutically acceptable salts thereof, of formula (I-M-1):
  • the present disclosure provides compounds, or pharmaceutically acceptable salts thereof, of formula (I-M-2):
  • the present disclosure provides compounds, or pharmaceutically acceptable salts thereof, of formula (I-M-3):
  • the present disclosure provides compounds, or pharmaceutically acceptable salts thereof, of formula (I-M-4):
  • the disclosure relates to a compound of formula (I), (I-1), (I-2), (I-3), or (I-4), or a pharmaceutically acceptable salt thereof, wherein Ar 1 is independently phenylene or 5-6 membered heteroarylene, wherein said phenylene or heteroarylene is substituted with m R 1 groups.
  • Ar 1 is phenylene substituted with m R 1 groups.
  • Ar 1 is phenylene substituted with 1-2 R 1 groups selected from the group consisting of halo, cyano, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 hydroxyalkyl.
  • Ar 1 is phenylene. In some embodiments, Ar 1 is 5-6 membered heteroarylene substituted with m R 1 groups. In some embodiments, Ar 1 is 5-6 membered heteroarylene substituted with 1-2 R 1 groups selected from the group consisting of halo, cyano, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 hydroxyalkyl. In some embodiments, Ar 1 is 5-membered heteroarylene substituted with m R 1 groups. In some embodiments, Ar 1 is pyrazole. In some embodiments, Ar 1 is thiazole. In some embodiments, Ar 1 is 6-membered heteroarylene substituted with m R 1 groups.
  • the disclosure relates to a compound of formula (I), (I-1), (I-2), (I-3), (1-4), (I-M), (I-M-1), (I-M-2), (I-M-3), or (I-M-4), or a pharmaceutically acceptable salt thereof, wherein Ar 2 is independently phenylene or 5-10 membered heteroarylene, wherein said phenylene or heteroarylene is substituted with n R 2 groups. In some embodiments, Ar 2 is phenylene or 5-6 membered heteroarylene, wherein said phenylene or heteroarylene is substituted with n R 2 groups. In some embodiments, Ar 2 is phenylene substituted with n R 2 groups.
  • Ar 2 is phenylene substituted with 1-2 R 2 groups selected from the group consisting of halo, cyano, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 hydroxyalkyl.
  • Ar 2 is phenylene.
  • Ar 2 is 5-10 membered heteroarylene substituted with n R 2 groups.
  • Ar 2 is 5-6 membered heteroarylene substituted with 1-2 R 2 groups selected from the group consisting of halo, cyano, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 hydroxyalkyl.
  • Ar 2 is 5-membered heteroarylene substituted with n R 2 groups.
  • Ar 2 is 6-membered heteroarylene substituted with n R 2 groups.
  • Ar 2 is pyridine.
  • Ar 2 is 7-membered heteroarylene substituted with n R 2 groups.
  • Ar 2 is 8-membered heteroarylene substituted with n R 2 groups. In some embodiments, Ar 2 is 9-membered heteroarylene substituted with n R 2 groups. In some embodiments, Ar 2 is 10-membered heteroarylene substituted with n R 2 groups.
  • the disclosure relates to a compound of formula (I), (I-1), (I-2), (I-3), (I-4), (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-B), (I-B-1), (I-B-2), (I-B-3), (I-B-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), (I-L-2), (I-M), (I-M-1), (I-M-2), (I-M-3), or (I-M-4), or a pharmaceutically acceptable salt thereof, wherein L is —O—, —S—, —NR 3 —, —C(R 4 ) 2 —, —S(O) 2 —, or —S(O)—.
  • L is —O—, —S—, or —NH—. In some embodiments, L is —O—. In some embodiments, L is —S—. In some embodiments, L is —NR 3 —. In some embodiments, L is —NH—. In some embodiments, L is —C(R 4 ) 2 —. In some embodiments, L is —CH 2 —. In some embodiments, L is —S(O) 2 —. In some embodiments, L is —S(O)—.
  • the disclosure relates to a compound of formula (I), (I-1), (I-2), (I-3), (I-4), (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-B), (I-B-1), (I-B-2), (I-B-3), (I-B-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), (I-L-2), (I-M), (I-M-1), (I-M-2), (I-M-3), or (I-M-4), or a pharmaceutically acceptable salt thereof, wherein M is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroary
  • M is 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein said cycloalkyl, phenyl, or heteroaryl is substituted with p R 5 groups.
  • M is C 1 -C 6 alkyl.
  • M is C 1 -C 6 haloalkyl.
  • M is 3-6 membered cycloalkyl substituted with p R 5 groups.
  • M is 3-6 membered cycloalkyl.
  • M is 3-6 membered cycloalkyl substituted with 1-2 R 5 groups selected from the group consisting of halo, cyano, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 hydroxyalkyl.
  • M is phenyl substituted with p R 5 groups. In some embodiments, M is phenyl.
  • M is phenyl substituted with 1-2 R 5 groups selected from the group consisting of halo, cyano, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, and C 1 -C 6 hydroxyalkyl.
  • M is phenyl substituted with fluoro.
  • M is 5-6 membered heteroaryl substituted with p R 5 groups. In some embodiments, M is 5-6 membered heteroaryl.
  • M is 5-6 membered heteroaryl substituted with 1-2 R 5 groups selected from the group consisting of halo, cyano, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 hydroxyalkyl.
  • the disclosure relates to a compound of formula (I), (I-1), (I-2), (I-3), (I-4), (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-B), (I-B-1), (I-B-2), (I-B-3), (I-B-4), (I-C), (I-C-1), (I-C-2), (I-C-3), (I-C-4), (I-C-a), (I-C-b), (I-C-c), (I-C-d), (I-C-e), (I-C-f), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), (I-L-2), (I-M), (I-M-1), (I-M-2), (I-M), (I
  • each occurrence of R 1 is independently halo, cyano, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 hydroxyalkyl.
  • each occurrence of R 1 is independently halo (e.g., fluoro, chloro, bromo, or iodo).
  • each occurrence of R 1 is fluoro.
  • each occurrence of R 1 is cyano.
  • each occurrence of R 1 is hydroxyl.
  • each occurrence of R 1 is C 1 -C 6 alkyl.
  • each occurrence of R 1 is C 1 -C 6 alkoxy. In some embodiments, each occurrence of R 1 is C 1 -C 6 haloalkyl. In some embodiments, each occurrence of R 1 is C 1 -C 6 hydroxyalkyl. In some embodiments, each occurrence of R 2 is independently halo, cyano, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 hydroxyalkyl. In some embodiments, each occurrence of R 2 is independently halo (e.g., fluoro, chloro, bromo, or iodo).
  • each occurrence of R 2 is fluoro. In some embodiments, each occurrence of R 2 is cyano. In some embodiments, each occurrence of R 2 is hydroxyl. In some embodiments, each occurrence of R 2 is C 1 -C 6 alkyl. In some embodiments, each occurrence of R 2 is C 1 -C 6 alkoxy. In some embodiments, each occurrence of R 2 is C 1 -C 6 haloalkyl. In some embodiments, each occurrence of R 2 is C 1 -C 6 hydroxyalkyl.
  • each occurrence of R 5 is independently halo, cyano, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 hydroxyalkyl.
  • each occurrence of R 5 is independently halo (e.g., fluoro, chloro, bromo, or iodo).
  • each occurrence of R 5 is fluoro.
  • each occurrence of R 5 is cyano.
  • each occurrence of R 5 is hydroxyl.
  • each occurrence of R 5 is C 1 -C 6 alkyl.
  • each occurrence of R 5 is C 1 -C 6 alkoxy. In some embodiments, each occurrence of R 5 is C 1 -C 6 haloalkyl. In some embodiments, each occurrence of R 5 is C 1 -C 6 hydroxyalkyl.
  • the disclosure relates to a compound of formula (I), (I-1), (I-2), (I-3), (I-4), (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-B), (I-B-1), (I-B-2), (I-B-3), (I-B-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), (I-L-2), (I-M), (I-M-1), (I-M-2), (I-M-3), or (I-M-4), or a pharmaceutically acceptable salt thereof, wherein R 3 is H, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments, R 3 is H. In some embodiments, R 3 is C 1 -C 6 al
  • the disclosure relates to a compound of formula (I), (I-1), (I-2), (I-3), (I-4), (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-B), (I-B-1), (I-B-2), (I-B-3), (I-B-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), (I-L-2), (I-M), (I-M-1), (I-M-2), (I-M-3), or (I-M-4), or a pharmaceutically acceptable salt thereof, wherein each R 4 is independently H, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl, or two R 4 groups together with the carbon atom to which they are attached form a
  • each R 4 is H. In some embodiments, two R 4 groups together with the carbon atom to which they are attached form a 3-6 membered cycloalkyl. In some embodiments, two R 4 groups together with the carbon atom to which they are attached form a 3-6 membered heterocycloalkyl.
  • the disclosure relates to a compound of formula (I), (I-1), (I-2), (I-3), (I-4), (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-B), (I-B-1), (I-B-2), (I-B-3), (I-B-4), (I-C), (I-C-1), (I-C-2), (I-C-3), (I-C-4), (I-C-a), (I-C-b), (I-C-c), (I-C-d), (I-C-e), (I-C-f), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), (I-L-2), (I-M), (I-M-1), (I-M-2), (I-M), (I
  • each R 6 is independently optionally substituted 5-10 membered heteroaryl. In some embodiments, each R 6 is independently optionally substituted 4-10 membered heterocycloalkyl. In some embodiments, each R 6 is independently optionally substituted 6-10 membered aryl. In some embodiments, each R 6 is independently optionally substituted 3-8 membered cycloalkyl.
  • the disclosure relates to a compound of formula (I), (I-1), (I-2), (I-3), (I-4), (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-B), (I-B-1), (I-B-2), (I-B-3), (I-B-4), (I-C), (I-C-1), (I-C-2), (I-C-3), (I-C-4), (I-C-a), (I-C-b), (I-C-c), (I-C-d), (I-C-e), (I-C-f), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), (I-L-2), (I-M), (I.
  • each R 7 , R 8 , and R 9 is independently hydrogen or C 1 -C 6 alkyl. In some embodiments, each R 7 , R 8 , and R 9 is independently hydrogen.
  • the disclosure relates to a compound of formula (I), (I-1), (I-2), (I-3), (I-4), (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-B), (I-B-1), (I-B-2), (I-B-3), (I-B-4), (I.
  • each R 10 , R 11 , and R 12 is independently hydrogen, C 1 -C 6 alkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl, or 3-8 membered cycloalkyl. In some embodiments, each R 10 , R 11 , and R 12 is independently hydrogen.
  • the disclosure relates to a compound of formula (I), (I-1), (I-2), (1-3), or (1-4), or a pharmaceutically acceptable salt thereof, wherein m is 0-4 (i.e., m is 0, 1, 2, 3, or 4). In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 1 or 2.
  • the disclosure relates to a compound of formula (I), (I-1), (I-2), (I-3), (I-4), (I-C), (I-C-1), (I-C-2), (I-C-3), (I-C-4), (I-C-a), (I-C-b), (I-C-c), (I-C-d), (I-C-e), (I-C-f), (I-M), (I-M-1), (I-M-2), (I-M-3), or (I-M-4), or a pharmaceutically acceptable salt thereof, wherein n is 0-4 (i.e., n is 0, 1, 2, 3, or 4). In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 1 or 2.
  • the disclosure relates to a compound of formula (I), (I-1), (I-2), (I-3), (I-4), (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-B), (I-B-1), (I-B-2), (I-B-3), (I-B-4), (I-C), (I-C-1), (I-C-2), (I-C-3), (I-C-4), (I-C-a), (I-C-b), (I-C-c), (I-C-d), (I-C-e), (I-C-f), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), (I-L-2), (I-M), (I-M-1), (I-M-2), (I-M), (I
  • p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 0, 1, or 2. In some embodiments, p is 1 or 2. In some embodiments, n and p are both 0. In some embodiments, m and n are both 0. In some embodiments, m and n are both 0. In some embodiments, m, n, and p are 0. In some embodiments, m and n are 0, and p is 1.
  • the disclosure relates to a compound of formula (I), (I-A), (I-B), (I-C), (I-D), (I-E), or (I-M), or a pharmaceutically acceptable salt thereof, wherein R a and R b form a C 1 -C 4 alkylene group between the atoms to which they are attached, wherein said C 1 -C 4 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C 1 -C 3 alkyl, and C 1 -C 3 haloalkyl.
  • R a and R b form a C 1 -C 4 alkylene group between the atoms to which they are attached; and R c , R d , R e , R f , R g , and R h are each hydrogen. In some embodiments, R a and R b form a C 1 alkylene group between the atoms to which they are attached; and R c , R d , R e , R f , R g , and R h are each hydrogen.
  • R a and R b form a C 2 alkylene group between the atoms to which they are attached; and R c , R d , R e , R f , R g , and R h are each hydrogen. In some embodiments, R a and R b form a C 3 alkylene group between the atoms to which they are attached; and R c , R d , R e , R f , R g , and R h are each hydrogen.
  • R a and R b form a C 4 alkylene group between the atoms to which they are attached; and R c , R d , R e , R f , R g , and R h are each hydrogen.
  • the disclosure relates to a compound of formula (I), (I-A), (I-B), (I-C), (I-D), (I-E), or (I-M), or a pharmaceutically acceptable salt thereof, wherein R a and R e form a C 1 -C 2 alkylene group between the atoms to which they are attached, wherein said C 1 -C 2 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C 1 -C 3 alkyl, and C 1 -C 3 haloalkyl.
  • R a and R e form a C 1 -C 2 alkylene group between the atoms to which they are attached; and R b , R c , R d , R e , R f , and R h are each hydrogen.
  • R a and R b form a C 1 alkylene group between the atoms to which they are attached; and R b , R c , R d , R f , R g , and R h are each hydrogen.
  • R a and R e form a C 2 alkylene group between the atoms to which they are attached; and R b , R c , R d , R f , R g , and R h are each hydrogen.
  • the disclosure relates to a compound of formula (I), (I-A), (I-B), (I-C), (I-D), (I-E), or (I-M), or a pharmaceutically acceptable salt thereof, wherein R a and R g form a C 1 -C 3 alkylene group between the atoms to which they are attached, wherein said C 1 -C 3 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C 1 -C 3 alkyl, and C 1 -C 3 haloalkyl.
  • R a and R g form a C 1 -C 3 alkylene group between the atoms to which they are attached; and R b , R c , R d , R e , R f , and R h are each hydrogen.
  • R a and R g form a C 1 alkylene group between the atoms to which they are attached; and R b , R c , R d , R e , R f , and R h are each hydrogen.
  • R a and R g form a C 2 alkylene group between the atoms to which they are attached; and R b , R c , R d , R e , R f , and R h are each hydrogen.
  • R a and R g form a C 3 alkylene group between the atoms to which they are attached; and R b , R c , R d , R e , R f , and R h are each hydrogen.
  • the disclosure relates to a compound of formula (I), (I-A), (I-B), (I-C), (I-D), (I-E), or (I-M), or a pharmaceutically acceptable salt thereof, wherein R b and R c form a C 1 -C 4 alkylene group between the atoms to which they are attached, wherein said C 1 -C 4 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C 1 -C 3 alkyl, and C 1 -C 3 haloalkyl.
  • R b and R c form a C 1 -C 4 alkylene group between the atoms to which they are attached; and R a , R d , R e , R f , R g , and R h are each hydrogen.
  • R b and R c form a C 1 -C 3 alkylene group between the atoms to which they are attached; and R a , R d , R c , R f , R g , and R h are each hydrogen.
  • R b and R c form a C 1 alkylene group between the atoms to which they are attached; and R a , R d , R e , R f , R g , and R h are each hydrogen.
  • R b and R c form a C 2 alkylene group between the atoms to which they are attached; and R a , R d , R e , R f , R g , and R h are each hydrogen.
  • R b and R c form a C 3 alkylene group between the atoms to which they are attached; and R a , R d , R e , R f , R g , and R h are each hydrogen. In some embodiments, R b and R c form a C 4 alkylene group between the atoms to which they are attached; and R a , R d , R e , R f , R g , and R h are each hydrogen.
  • the disclosure relates to a compound of formula (I), (I-A), (I-B), (I-C), (I-D), (I-E), or (I-M), or a pharmaceutically acceptable salt thereof, wherein R b and R e form a C 1 -C 3 alkylene group between the atoms to which they are attached, wherein said C 1 -C 3 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C 1 -C 3 alkyl, and C 1 -C 3 haloalkyl.
  • R b and R e form a C 1 -C 3 alkylene group between the atoms to which they are attached; and R a , R c , R d , R f , R g , and R h are each hydrogen.
  • R b and R e form a C 1 alkylene group between the atoms to which they are attached; and R a , R c , R d , R f , R g , and R h are each hydrogen.
  • R b and R c form a C 2 alkylene group between the atoms to which they are attached; and R a , R c , R d , R f , R g , and R h are each hydrogen.
  • R b and R e form a C 3 alkylene group between the atoms to which they are attached; and R a , R c , R d , R f , R g , and R h are each hydrogen.
  • the disclosure relates to a compound of formula (I), (I-A), (I-B), (I-C), (I-D), (I-E), or (I-M), or a pharmaceutically acceptable salt thereof, wherein R b and R g form a C 1 -C 4 alkylene group between the atoms to which they are attached, wherein said C 1 -C 4 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C 1 -C 3 alkyl, and C 1 -C 3 haloalkyl.
  • R b and R g form a C 1 -C 4 alkylene group between the atoms to which they are attached; and R a , R c , R d , R e , R f , and R h are each hydrogen.
  • R b and R g form a C 1 alkylene group between the atoms to which they are attached; and R a , R c , R d , R e , R f , and R h are each hydrogen.
  • R b and R g form a C 2 alkylene group between the atoms to which they are attached; and R a , R c , R d , R e , R f , and R h are each hydrogen.
  • R b and R g form a C 3 alkylene group between the atoms to which they are attached; and R a , R c , R d , R e , R f , and R h are each hydrogen.
  • R b and R g form a C 4 alkylene group between the atoms to which they are attached; and R a , R c , R d , R e , R f , and R h are each hydrogen.
  • the disclosure relates to a compound of formula (I), (I-A), (I-B), (I-C), (I-D), (I-E), or (I-M), or a pharmaceutically acceptable salt thereof, wherein R c and R d together with the atom to which they are attached, form a 3-6 membered cycloalkyl or heterocycloalkyl, wherein said 3-6 membered cycloalkyl or heterocycloalkyl is substituted with 0-4 substituents selected from the group consisting of halogen, C 1 -C 3 alkyl, and C 1 -C 3 haloalkyl.
  • R c and R d together with the atom to which they are attached form a 3-6 membered cycloalkyl or heterocycloalkyl; and R a , R b , R e , R f , R g , and R h are each hydrogen.
  • R c and R d together with the atom to which they are attached form a 3 membered cycloalkyl or a 4 membered heterocycloalkyl; and R a , R b , R e , R f , R g , and R h are each hydrogen.
  • R c and R d together with the atom to which they are attached form a 3-6 membered cycloalkyl; and R a , R b , R e , R f , R g , and R h are each hydrogen. In some embodiments, R c and R d together with the atom to which they are attached, form a 3 membered cycloalkyl; and R a , R b , R e , R f , R g , and R h are each hydrogen.
  • R c and R d together with the atom to which they are attached form a 4 membered cycloalkyl; and R a , R b , R e , R f , R g , and R h are each hydrogen. In some embodiments, R c and R d together with the atom to which they are attached, form a 5 membered cycloalkyl; and R a , R b , R e , R f , R g , and R h are each hydrogen.
  • R c and R d together with the atom to which they are attached form a 6 membered cycloalkyl; and R a , R b , R c , R f , R g , and R h are each hydrogen. In some embodiments, R c and R d together with the atom to which they are attached, form a 3-6 membered heterocycloalkyl ring; and R a , R b , R e , R f , R g , and R h are each hydrogen.
  • R c and R d together with the atom to which they are attached form a 3-6 membered heterocycloalkyl ring, wherein the 3-6 membered heterocycloalkyl ring contains 0, S, or NH; and R a , R b , R e , R f , R g , and R h are each hydrogen.
  • R c and R d together with the atom to which they are attached form a 3 membered heterocycloalkyl ring; and R a , R b , R e , R f , R b , and R h are each hydrogen.
  • R c and R d together with the atom to which they are attached form a 4 membered heterocycloalkyl ring; and R a , R b , R e , R f , R g , and R h are each hydrogen.
  • R c and R d together with the atom to which they are attached form an oxetane ring; and R a , R b , R e , R f , R g , and R h are each hydrogen.
  • R c and R d together with the atom to which they are attached form a 5 membered heterocycloalkyl ring; and R a , R b , R e , R f , R g , and R h are each hydrogen.
  • R c and R d together with the atom to which they are attached form a 6 membered heterocycloalkyl ring; and R a , R b , R e , R f , R g , and R h are each hydrogen.
  • R e and R d together form ⁇ O.
  • R c and R d together form ⁇ O; and R a , R b , R e , R f , R g , and R h are each hydrogen.
  • the disclosure relates to a compound of formula (I), (I-A), (I-B), (I-C), (I-D), (I-E), or (I-M), or a pharmaceutically acceptable salt thereof, wherein R c and R e form a C 1 -C 4 alkylene group between the atoms to which they are attached, wherein said C 1 -C 4 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C 1 -C 3 alkyl, and C 1 -C 3 haloalkyl.
  • R c and R e form a C 1 -C 4 alkylene group between the atoms to which they are attached; and R a , R b , R d , R f , R g , and R h are each hydrogen.
  • R c and R e form a C 1 alkylene group between the atoms to which they are attached; and R a , R b , R d , R f , R g , and R h are each hydrogen.
  • R c and R e form a C 2 alkylene group between the atoms to which they are attached; and R a , R b , R d , R f , R g , and R h are each hydrogen.
  • R c and R e form a C 3 alkylene group between the atoms to which they are attached; and R a , R b , R d , R f , R g , and R h are each hydrogen.
  • R c and R e form a C 4 alkylene group between the atoms to which they are attached; and R a , R b , R d , R f , R g , and R h are each hydrogen.
  • the disclosure relates to a compound of formula (I), (I-A), (I-B), (I-C), (I-D), (I-E), or (I-M), or a pharmaceutically acceptable salt thereof, wherein R c and R g form a C 1 -C 3 alkylene group between the atoms to which they are attached, wherein said C 1 -C 3 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C 1 -C 3 alkyl, and C 1 -C 3 haloalkyl.
  • R c and R g form a C 1 -C 3 alkylene group between the atoms to which they are attached; and R a , R b , R d , R e , R f , and R h are each hydrogen.
  • R c and R g form a C 1 -C 2 alkylene group between the atoms to which they are attached; and R a , R b , R d , R e , R f , and R h are each hydrogen.
  • R c and R g form a C 1 alkylene group between the atoms to which they are attached; and R a , R b , R d , R e , R f , and R h are each hydrogen.
  • R c and R g form a C 2 alkylene group between the atoms to which they are attached; and R a , R b , R d , R e , R f , and R h are each hydrogen.
  • R c and R g form a C 3 alkylene group between the atoms to which they are attached; and R a , R b , R d , R e , R f , and R h are each hydrogen.
  • the disclosure relates to a compound of formula (I), (I-A), (I-B), (I-C), (I-D), (I-E), or (I-M), or a pharmaceutically acceptable salt thereof, wherein R e and R f together with the atom to which they are attached, form a 3-6 membered cycloalkyl or heterocycloalkyl, wherein said 3-6 membered cycloalkyl or heterocycloalkyl is substituted with 0-4 substituents selected from the group consisting of halogen, C 1 -C 3 alkyl, and C 1 -C 3 haloalkyl.
  • R e and R f together with the atom to which they are attached form a 3-6 membered cycloalkyl or heterocycloalkyl; and R a , R b , R c , R d , R g , and R h are each hydrogen.
  • R e and R f together with the atom to which they are attached form a 3-6 membered cycloalkyl; and R a , R b , R c , R d , R g , and R h are each hydrogen.
  • R e and R f together with the atom to which they are attached form a 3 membered cycloalkyl; and R a , R b , R c , R d , R g , and R h are each hydrogen. In some embodiments, R e and R f together with the atom to which they are attached, form a 4 membered cycloalkyl; and R a , R b , R c , R d , R g , and R h are each hydrogen.
  • R e and R f together with the atom to which they are attached form a 5 membered cycloalkyl; and R a , R b , R c , R d , R g , and R h are each hydrogen. In some embodiments, R e and R f together with the atom to which they are attached, form a 6 membered cycloalkyl; and R a , R b , R c , R d , R g , and R h are each hydrogen.
  • R e and R f together with the atom to which they are attached form a 3-6 membered heterocycloalkyl ring; and R a , R b , R c , R d , R g , and R h are each hydrogen.
  • R e and R f together with the atom to which they are attached form a 3-6 membered heterocycloalkyl ring, wherein the 3-6 membered heterocycloalkyl ring contains 0, S, or NH; and R a , R b , R c , R d , R g , and R h are each hydrogen.
  • R e and R f together with the atom to which they are attached form a 3 membered heterocycloalkyl ring; and R a , R b , R e , R d , R g , and R h are each hydrogen. In some embodiments, R e and R f together with the atom to which they are attached, form a 4 membered heterocycloalkyl ring; and R a , R b , R c , R d , R g , and R h are each hydrogen.
  • R e and R f together with the atom to which they are attached form an oxetane ring; and R a , R b , R c , R d , R g , and R h are each hydrogen. In some embodiments, R e and R f together with the atom to which they are attached, form a 5 membered heterocycloalkyl ring; and R a , R b , R c , R d , R g , and R h are each hydrogen.
  • the disclosure relates to a compound of formula (I), (I-A), (I-B), (I-C), (I-D), (I-E), or (I-M), or a pharmaceutically acceptable salt thereof, wherein R e and R g form a C 1 -C 3 alkylene group between the atoms to which they are attached, wherein said C 1 -C 3 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C 1 -C 3 alkyl, and C 1 -C 3 haloalkyl.
  • R e and R g form a C 1 -C 3 alkylene group between the atoms to which they are attached; and R a , R b , R c , R d , R f , and R h are each hydrogen.
  • R e and R g form a C 1 alkylene group between the atoms to which they are attached; and R a , R b , R c , R d , R f , and R h are each hydrogen.
  • R e and R g form a C 2 alkylene group between the atoms to which they are attached; and R a , R b , R c , R d , R f , and R h are each hydrogen.
  • R e and R g form a C 3 alkylene group between the atoms to which they are attached; and R a , R b , R c , R d , R f , and R h are each hydrogen.
  • the disclosure relates to a compound of formula (I), (I-A), (I-B), (I-C), (I-D), (I-E), or (I-M), or a pharmaceutically acceptable salt thereof, wherein R g and R h together with the atom to which they are attached, form a 3-6 membered cycloalkyl or heterocycloalkyl, wherein said 3-6 membered cycloalkyl or heterocycloalkyl is substituted with 0-4 substituents selected from the group consisting of halogen, C 1 -C 3 alkyl, and C 1 -C 3 haloalkyl.
  • R g and R h together with the atom to which they are attached form a 3-6 membered cycloalkyl or heterocycloalkyl; and R a , R b , R c , R d , R e , and R f are each hydrogen.
  • R g and R h together with the atom to which they are attached form a 3-6 membered cycloalkyl; and R a , R b , R c , R d , R e , and R f are each hydrogen.
  • R g and R h together with the atom to which they are attached form a 3 membered cycloalkyl; and R a , R b , R c , R d , R e , and R f are each hydrogen.
  • R g and R h together with the atom to which they are attached form a 4 membered cycloalkyl; and R a , R b , R c , R d , R e , and R f are each hydrogen.
  • R g and R h together with the atom to which they are attached form a 5 membered cycloalkyl; and R a , R b , R c , R d , R e , and R f are each hydrogen.
  • R g and R h together with the atom to which they are attached form a 6 membered cycloalkyl; and R a , R b , R c , R d , R e , and R f are each hydrogen.
  • R g and R h together with the atom to which they are attached form a 3-6 membered heterocycloalkyl ring; and R a , R b , R c , R d , R e , and R f are each hydrogen.
  • R g and R h together with the atom to which they are attached form a 3-6 membered heterocycloalkyl ring, wherein the 3-6 membered heterocycloalkyl ring contains 0, S, or NH; and R a , R b , R c , R d , R e , and R f are each hydrogen.
  • R g and R h together with the atom to which they are attached form a 3 membered heterocycloalkyl ring; and R a , R b , R c , R d , R e , and R f are each hydrogen.
  • R g and R h together with the atom to which they are attached form a 4 membered heterocycloalkyl ring; and R a , R b , R c , R d , R e , and R f are each hydrogen.
  • R g and R h together with the atom to which they are attached form an oxetane ring; and R a , R b , R c , R d , R c , and R f are each hydrogen.
  • R g and R h together with the atom to which they are attached form a 5 membered heterocycloalkyl ring; and R a , R b , R c , R d , R e , and R f are each hydrogen.
  • the disclosure relates to a compound of formula (I), (I-A), (I-B), (I-C), (I-D), (I-E), or (I-M), or a pharmaceutically acceptable salt thereof, wherein R a , R b , R c , R d , R e , R f , R g , and R h are defined as follows:
  • the disclosure relates to a compound of formula (I), (I-A), (I-B), (I-C), (I-D), (I-E), or (I-M), or a pharmaceutically acceptable salt thereof, wherein R a , R b , R e , R d , R e , R f , R g , and R h are defined as follows:
  • the disclosure relates to a compound of formula (I), (I-A), (I-B), (I-C), (I-D), (I-E), or (I-M), or a pharmaceutically acceptable salt thereof, wherein R a , R b , R e , R d , R e , R f , R g , and R h are defined as follows:
  • the disclosure relates to a compound of formula (I), (I-A), (I-B), (I-C), (I-D), (I-E), or (I-M), or a pharmaceutically acceptable salt thereof, wherein R a , R b , R c , R d , R e , R f , R g , and R h are defined as follows:
  • the disclosure relates to a compound of formula (I), (I-A), (I-B), (I-C), (I-D), (I-E), or (I-M), or a pharmaceutically acceptable salt thereof, wherein
  • the disclosure relates to a compound of formula (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-B), (I-B-1), (I-B-2), (I-B-3), (I-B-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), (I-L-2), (I-M), (I-M-1), (I-M-2), (I-M-3), or (I-M-4), or a pharmaceutically acceptable salt thereof, wherein X 1 is C or N. In some embodiments, X 1 is C. In some embodiments, X 1 is N.
  • the disclosure relates to a compound of formula (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-B), (I-B-1), (I-B-2), (I-B-3), (I-B-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), (I-L-2), (I-M), (I-M-1), (I-M-2), (I-M-3), or (I-M-4), or a pharmaceutically acceptable salt thereof, wherein X 2 is CH, CR 1 , O, S, N, NH, or NR 1 , as valency permits.
  • X 2 is CH. In some embodiments, X 2 is CR 1 . In some embodiments, X 2 is O. In some embodiments, X 2 is S. In some embodiments, X 2 is N. In some embodiments, X 2 is NH. In some embodiments, X 2 is NR 1 .
  • the disclosure relates to a compound of formula (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-B), (I-B-1), (I-B-2), (I-B-3), (I-B-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), (I-L-2), (I-M), (I-M-1), (I-M-2), (I-M-3), or (I-M-4), or a pharmaceutically acceptable salt thereof, wherein X 3 is CH, CR 1 , O, S, N, NH, or NR 1 , as valency permits.
  • X 3 is CH. In some embodiments, X 3 is CR 1 . In some embodiments, X 3 is O. In some embodiments, X 3 is S. In some embodiments, X 3 is N. In some embodiments, X 3 is NH. In some embodiments, X 3 is NR 1 .
  • the disclosure relates to a compound of formula (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-B), (I-B-1), (I-B-2), (I-B-3), (I-B-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), (I-L-2), (I-M), (I-M-1), (I-M-2), (I-M-3), or (I-M-4), or a pharmaceutically acceptable salt thereof, wherein X 4 is C or N. In some embodiments, X 4 is C. In some embodiments, X 4 is N.
  • the disclosure relates to a compound of formula (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), (I-L-2), (I-M), (I-M-1), (I-M-2), (I-M-3), or (I-M-4), or a pharmaceutically acceptable salt thereof, wherein X 5 is a bond, CH, CR 1 , O, S, N, NH, or NR 1 , as valency permits.
  • X 5 is a bond. In some embodiments, X 5 is CH. In some embodiments, X 5 is CR 1 . In some embodiments, X 5 is O. In some embodiments, X 5 is S. In some embodiments, X 5 is N. In some embodiments, X 5 is NH. In some embodiments, X 5 is NR 1 .
  • the disclosure relates to a compound of formula (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-B), (I-B-1), (I-B-2), (I-B-3), (I-B-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), (I-L-2), (I-M), (I-M-1), (I-M-2), (I-M-3), or (I-M-4), or a pharmaceutically acceptable salt thereof, wherein X 6 is CH, CR 1 , O, S, N, NH, or NR 1 , as valency permits.
  • X 6 is CH. In some embodiments, X 6 is CR 1 . In some embodiments, X 6 is O. In some embodiments, X 6 is S. In some embodiments, X 6 is N. In some embodiments, X 6 is NH. In some embodiments, X 6 is NR 1 .
  • the disclosure relates to a compound of formula (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), (I-L-2), (I-M), (I-M-1), (I-M-2), (I-M-3), or (I-M-4), or a pharmaceutically acceptable salt thereof, wherein X 1 is C; X 2 is N; X 3 is NH; X 4 is C; X 5 is a bond; and X 6 is CH.
  • the disclosure relates to a compound of formula (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), (I-L-2), (I-M), (I-M-1), (I-M-2), (I-M-3), or (I-M-4), or a pharmaceutically acceptable salt thereof, wherein X 1 is C; X 2 is N; X 3 is CH; X 4 is C; X 5 is a bond; and X 6 is S.
  • the disclosure relates to a compound of formula (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), (I-L-2), (I-M), (I-M-1), (I-M-2), (I-M-3), or (I-M-4), or a pharmaceutically acceptable salt thereof, wherein X 1 is C; X 2 is CH; X 3 is CH; X 4 is C; X 5 is CH; and X 6 is C.
  • the disclosure relates to a compound of formula (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-F7-1), (I-F7-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), or (I-L-2), or a pharmaceutically acceptable salt thereof, wherein Y 1 is C or N. In some embodiments, Y 1 is C. In some embodiments, Y 1 is N.
  • the disclosure relates to a compound of formula (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), or (I-L-2), or a pharmaceutically acceptable salt thereof, wherein Y 2 is C or N. In some embodiments, Y 2 is C. In some embodiments, Y 2 is N.
  • the disclosure relates to a compound of formula (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-B), (I-B-1), (I-B-2), (I-B-3), (I-B-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), or (I-L-2), or a pharmaceutically acceptable salt thereof, wherein Y 3 is CH, CR 2 , O, S, N, NH, or NR 2 , as valency permits.
  • Y 3 is CH. In some embodiments, Y 3 is CR 2 . In some embodiments, Y 3 is 0. In some embodiments, Y 3 is S. In some embodiments, Y 3 is N. In some embodiments, Y 3 is NH. In some embodiments, Y 3 is NR 2 .
  • the disclosure relates to a compound of formula (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-B), (I-B-1), (I-B-2), (I-B-3), (I-B-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), or (I-L-2), or a pharmaceutically acceptable salt thereof, wherein Y 4 is a bond, CH, CR 2 , O, S, N, NH, or NR 2 , as valency permits.
  • Y 4 is a bond. In some embodiments, Y 4 is CH. In some embodiments, Y 4 is CR 2 . In some embodiments, Y 4 is O. In some embodiments, Y 4 is S. In some embodiments, Y 4 is N. In some embodiments, Y 4 is NH. In some embodiments, Y 4 is NR 2 .
  • the disclosure relates to a compound of formula (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-B), (I-B-1), (I-B-2), (I-B-3), (I-B-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), or (I-L-2), or a pharmaceutically acceptable salt thereof, wherein Y 5 is CH, CR 2 , O, S, N, NH, or NR 2 , as valency permits.
  • Y 5 is CH. In some embodiments, Y 5 is CR 2 . In some embodiments, Y 5 is O. In some embodiments, Y 5 is S. In some embodiments, Y 5 is N. In some embodiments, Y 5 is NH. In some embodiments, Y 5 is NR 2 .
  • the disclosure relates to a compound of formula (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-B), (I-B-1), (I-B-2), (I-B-3), (I-B-4), (I-F7-1), (I-F7-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), or (I-L-2), or a pharmaceutically acceptable salt thereof, wherein Y 6 is CH, CR 2 , O, S, N, NH, or NR 2 , as valency permits.
  • Y 6 is CH. In some embodiments, Y 6 is CR 2 . In some embodiments, Y 6 is 0. In some embodiments, Y 6 is S. In some embodiments, Y 6 is N. In some embodiments, Y 6 is NH. In some embodiments, Y 6 is NR 2 .
  • the disclosure relates to a compound of formula (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), or (I-L-2), or a pharmaceutically acceptable salt thereof, wherein Y 1 is C; Y 2 is C; Y 3 is CH; Y 4 is CH; Y 5 is CH; and Y 6 is CH.
  • the disclosure relates to a compound of formula (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), or (I-L-2), or a pharmaceutically acceptable salt thereof, wherein Y 1 is C; Y 2 is C; Y 3 is CR 2 ; Y 4 is CH; Y 5 is CH; and Y 6 is CH.
  • the disclosure relates to a compound of formula (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-F7-1), (I-F7-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), or (I-L-2), or a pharmaceutically acceptable salt thereof, wherein Y 1 is C; Y 2 is C; Y 3 is CH; Y 4 is CR 2 ; Y 5 is CH; and Y 6 is CH.
  • the disclosure relates to a compound of formula (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), or (I-L-2), or a pharmaceutically acceptable salt thereof, wherein Y 1 is C; Y 2 is C; Y 3 is CH; Y 4 is CH; Y 5 is CR 2 ; and Y 6 is CH.
  • the disclosure relates to a compound of formula (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), or (I-L-2), or a pharmaceutically acceptable salt thereof, wherein Y 1 is C; Y 2 is C; Y 3 is N; Y 4 is CH; Y 5 is CH; and Y 6 is CR 2 .
  • the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein Y 1 is C; Y 2 is C; Y 3 is N; Y 4 is CH; Y 5 is CH; and Y 6 is CH.
  • the disclosure relates to a compound of formula (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), or (I-L-2), or a pharmaceutically acceptable salt thereof, wherein Y 1 is C; Y 2 is C; Y 3 is CH; Y 4 is N; Y 5 is CH; and Y 6 is CH.
  • the disclosure relates to a compound of formula (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), or (I-L-2), or a pharmaceutically acceptable salt thereof, wherein Y 1 is C; Y 2 is C; Y 3 is CH; Y 4 is CH; Y is N; and Y 6 is CH.
  • the disclosure relates to a compound of formula (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), or (I-L-2), or a pharmaceutically acceptable salt thereof, wherein Y 1 is C; Y 2 is C; Y 3 is CH; Y 4 is CH; Y 5 is CH; and Y 6 is N.
  • the disclosure relates to a compound of formula (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-B-1), (I-B-2), (I-B-3), (I-B-4), (I-C-1), (I-C-2), (I-C-3), (I-C-4), (I-M-1), (I-M-2), (I-M-3), or (I-M-4), or a pharmaceutically acceptable salt thereof, wherein R j , R k , R m , R n , R o , R p , R q , and R r , when present, are each independently hydrogen, halogen, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl. In some embodiments, R j , R k , R m , R n , R o , R p , R q , and R r , when present, are each hydrogen.
  • the disclosure relates to a compound of formula (I-B), (I-B-1), (I-B-2), (I-B-3), or (I-B-4), or a pharmaceutically acceptable salt thereof, wherein X 1 is C; X 2 is N; X 3 is NH; X 4 is C; and X 6 is CH.
  • the disclosure relates to a compound of formula (I-B), (I-B-1), (I-B-2), (I-B-3), or (I-B-4), or a pharmaceutically acceptable salt thereof, wherein X 1 is C; X 2 is N; X 3 is CH; X 4 is C; and X 6 is S.
  • the disclosure relates to a compound of formula (I-B), (I-B-1), (I-B-2), (I-B-3), or (I-B-4), or a pharmaceutically acceptable salt thereof, wherein Y 3 is CH; Y 4 is CH; Y 5 is CH; and Y 6 is CH.
  • the disclosure relates to a compound of formula (I-B), (I-B-1), (I-B-2), (I-B-3), or (I-B-4), or a pharmaceutically acceptable salt thereof, wherein Y 3 is CR 2 ; Y 4 is CH; Y 5 is CH; and Y 6 is CH.
  • the disclosure relates to a compound of formula (I-B), (I-B-1), (I-B-2), (I-B-3), or (I-B-4), or a pharmaceutically acceptable salt thereof, wherein Y 3 is CH; Y 4 is CR 2 ; Y 5 is CH; and Y 6 is CH.
  • the disclosure relates to a compound of formula (I-B), (I-B-1), (I-B-2), (I-B-3), or (I-B-4), or a pharmaceutically acceptable salt thereof, wherein Y 3 is CH; Y 4 is CH; Y 5 is CR 2 ; and Y 6 is CH.
  • the disclosure relates to a compound of formula (I-B), (I-B-1), (I-B-2), (I-B-3), or (I-B-4), or a pharmaceutically acceptable salt thereof, wherein Y 3 is CH; Y 4 is CH; Y 5 is CH; and Y 6 is CR 2 .
  • the disclosure relates to a compound of formula (I-B), (I-B-1), (I-B-2), (I-B-3), or (I-B-4), or a pharmaceutically acceptable salt thereof, wherein Y 3 is N; Y 4 is CH; Y 5 is CH; and Y 6 is CH.
  • the disclosure relates to a compound of formula (I-B), (I-B-1), (I-B-2), (I-B-3), or (I-B-4), or a pharmaceutically acceptable salt thereof, wherein Y 3 is CH; Y 4 is N; Y 5 is CH; and Y 6 is CH.
  • the disclosure relates to a compound of formula (I-B), (I-B-1), (I-B-2), (I-B-3), or (I-B-4), or a pharmaceutically acceptable salt thereof, wherein Y 3 is CH; Y 4 is CH; Y 5 is N; and Y 6 is CH.
  • the disclosure relates to a compound of formula (I-B), (I-B-1), (I-B-2), (I-B-3), or (I-B-4), or a pharmaceutically acceptable salt thereof, wherein Y 3 is CH; Y 4 is CH; Y 5 is CH; and Y 6 is N.
  • the disclosure relates to a compound provided herein, or a pharmaceutically acceptable salt thereof, that is a USP30 Inhibitor Compound having an IC50 value of ⁇ 1 ⁇ M and >0.001 ⁇ M as measured in a Ubiquitin-Rhodamine 110 Assay as described in Example 1.
  • the disclosure relates to a compound selected from Table 1, or a pharmaceutically acceptable salt thereof.
  • Table 1 Each pair of compounds listed in Table 1 (i.e., compounds 1-a and 1-b, compounds 2-a and 2-b, etc.) was obtained as a racemic mixture, and were then separated by chiral HPLC according to the procedure described in Example 2, Step 7, or a similar method, to obtain the individual compounds in substantially enantiomerically pure form.
  • the first compound i.e., compounds 1-a, 2-a, etc.
  • the second compound i.e., compounds 1-b, 2-b, etc.
  • the stereochemical descriptors reflect the relative stereochemistry of each compound.
  • each compound selected from Table 1, or a pharmaceutically acceptable salt thereof is present in a racemic mixture. In some embodiments, the compound selected from Table 1, or a pharmaceutically acceptable salt thereof, is present in substantially enantiomerically pure form.
  • the disclosure relates to a compound selected from Table 2, or a pharmaceutically acceptable salt thereof.
  • the compound, or a pharmaceutically acceptable salt thereof is present in a racemic mixture with its enantiomer.
  • the compound, or a pharmaceutically acceptable salt thereof is present in substantially enantiomerically pure form.
  • the disclosure relates to the enantiomer of a compound selected from Table 2, or a pharmaceutically acceptable salt thereof.
  • the enantiomer, or a pharmaceutically acceptable salt thereof is present in a racemic mixture.
  • the enantiomer, or a pharmaceutically acceptable salt thereof is present in substantially enantiomerically pure form.
  • a compound described herein is provided in non-salt form. In some embodiments, a compound described herein is provided as a pharmaceutically acceptable salt.
  • the disclosure relates to a compound, or a pharmaceutically acceptable salt thereof, prepared by a method comprising: preparing a compound of the present disclosure as a mixture of stereoisomers; separating the stereoisomers by chiral HPLC according to the procedure described in Example 2, Step 7; isolating one or more stereoisomers that are USP30 Inhibitor Compounds having an IC 50 value of ⁇ 1 ⁇ M as measured in a Ubiquitin-Rhodamine 110 Assay as described in Example 1; and optionally treating the isolated stereoisomer with an acid or base to afford a pharmaceutically acceptable salt thereof.
  • the compound is the 1 st eluting isomer. In some embodiments, the compound is the 2 nd eluting isomer. In some embodiments, the compound is the 3 rd eluting isomer. In some embodiments, the compound is the 4 th eluting isomer. In some embodiments, the compound is the 5 th , 6 th , 7 th , or 8 th eluting isomer.
  • a compound of the present disclosure, or a pharmaceutically acceptable salt thereof is a USP30 Inhibitor Compound having an IC 50 value of ⁇ 1 ⁇ M as measured in a Ubiquitin-Rhodamine 110 Assay as described in Example 1. In some embodiments, the IC 50 value is ⁇ 0.1 ⁇ M.
  • the disclosure also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising one or more compounds provided herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises a therapeutically effective amount of the one or more compounds, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition is for use in a method of treating a neurodegenerative disorder, such as Parkinson's Disease.
  • the compounds and pharmaceutically acceptable salts disclosed herein may be administered via any mode of administration for therapeutic agents, consistent with conventional pharmaceutical practices.
  • the pharmaceutical compositions reported herein can be provided in a unit dosage form.
  • the pharmaceutical compositions reported herein can be provided in an oral dosage form.
  • the pharmaceutical compositions described herein can be provided in a solid oral dosage form, such as a tablet, capsule, powder, or cachet.
  • compositions described herein can be prepared according to conventional mixing, granulating or coating methods.
  • oral dosage forms e.g., tablets
  • the pharmaceutical compositions described herein can contain from about 0.1% to about 99%, from about 5% to about 90%, or from about 1% to about 20% of the compound or pharmaceutically acceptable salt by weight or volume.
  • the pharmaceutically acceptable carriers employed in the pharmaceutical compositions described herein may include one or more pharmaceutical excipients, such as fillers, disintegrants, lubricants, glidants, anti-adherents, anti-statics, surfactants, or stabilizing additives.
  • Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate, talc, sugar or lactose. With some drugs, the presence of such additives promotes the stability and dispersibility of the agent in solution.
  • Suitable, but non-limiting, examples of stabilizing additives include gum acacia, gelatin, methyl cellulose, polyethylene glycol, carboxylic acids and salts thereof, and polylysine. In some embodiments, the stabilizing additives are gum acacia, gelatin and methyl cellulose. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pa.
  • compositions described herein may contain the compound or pharmaceutically acceptable salt in substantially pure form, such as at least 60% pure, more suitably at least 75% pure, preferably at least 85% pure and most preferably at least 98% pure (w/w).
  • the compounds and pharmaceutically acceptable salts described herein are preferably administered in a therapeutically effective amount (e.g., an amount having a suitable favorable therapeutic index).
  • a therapeutically effective amount e.g., an amount having a suitable favorable therapeutic index.
  • the amount and frequency of administration will be regulated according to the judgment of the attending clinician considering such factors as the age, gender, condition and size of the patient, as well as severity of the medical condition being treated; the route of administration; the renal or hepatic function of the patient; and the particular compound or pharmaceutically acceptable salt employed.
  • a physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
  • the total daily dosage may be divided and administered in portions during the day as required.
  • the present disclosure also provides uses of compounds of formula (I).
  • Compounds of formula (I) are useful in medicine.
  • compounds and compositions described herein are inhibitors of USP30.
  • such inhibition of USP30 can provide treatment of the symptoms and/or underlying causes of diseases or conditions associated with USP30 activity.
  • inhibitors of USP30 can be used to treat neurodegenerative and neurologic diseases or conditions, such as Parkinson's disease.
  • a disease or disorder associated with a ubiquitin-specific protease comprising administering to a patient in need thereof a therapeutically effective amount of a compound or composition provided herein.
  • the disease or disorder associated with a ubiquitin-specific protease is a neurodegenerative disease or disorder (e.g., Parkinson's disease).
  • the present disclosure also provides methods of inhibiting a ubiquitin-specific protease (e.g., USP30) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound or composition provided herein.
  • a ubiquitin-specific protease e.g., USP30
  • the present disclosure also provides methods of treating a neurodegenerative disease or disorder (e.g., Parkinson's disease) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound or composition provided herein.
  • a neurodegenerative disease or disorder e.g., Parkinson's disease
  • the present disclosure also provides compounds for use in method of inhibiting a ubiquitin-specific protease (e.g., USP30) in a patient in need thereof.
  • a ubiquitin-specific protease e.g., USP30
  • the present disclosure provides compounds for use in a method of treating a neurodegenerative disease or disorder (e.g., Parkinson's disease) in a patient in need thereof.
  • the compounds and pharmaceutically acceptable salts disclosed herein may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthetic schemes. In the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis”, Third edition, Wiley, New York 1999). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art.
  • the compounds of formula (I) can be synthesized by the methods outlined in Scheme 1, by the specific procedures discussed in Examples 2-4, and/or by methods otherwise known to one skilled in the art.
  • the starting materials for the synthesis described in Scheme 1 are commercially available or can be prepared by methods known to one skilled in the art.
  • R a , R b , R c , R d , R e , R f , R g , and R h are defined as follows:
  • R a , R b , R c , R d , R e , R f , R g , and R h are defined as follows:
  • R a , R b , R c , R d , R e , R f , R g , and R h are defined as follows:
  • R a , R b , R c , R d , R e , R f , R g , and R h are defined as follows:
  • R a , R b , R c , R d , R e , R f , and R g are defined as follows:
  • a pharmaceutical composition comprising the compound of any one of embodiments 1-36, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • a method of treating a neurodegenerative disorder in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the compound of any one of embodiments 1-36, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 37. 41. The method of embodiment 40, wherein the neurodegenerative disorder is Parkinson's Disease. 42. A compound of any one of embodiments 1-36, or a pharmaceutically acceptable salt thereof, for use in a method of inhibiting a ubiquitin-specific protease in a patient in need thereof. 43. The compound or pharmaceutically acceptable salt for use of embodiment 42, wherein the ubiquitin-specific protease is USP30. 44.
  • LCMS analyses were performed on a SHIMADZU LCMS consisting of an UFLC 20-AD and LCMS 2020 MS detector.
  • the column used was a Shim-pack XR-ODS, 2.2 ⁇ m, 3.0 ⁇ 50 mm.
  • the instrument uses reverse-phase conditions (acetonitrile/water, containing 0.05% ammonia).
  • the assay was performed in a final volume of 9 ⁇ L in assay buffer containing 20 mM Tris-HCl (pH 8.0, (IM Tris-HCl, pH 8.0 solution; Corning 46-031-CM)), 1 mM GSH (L-glutathione reduced, Sigma-Aldrich, G4251-100G), 0.03% BGG (0.22 ⁇ M filtered, Sigma, G7516-25G), and 0.01% Triton X-100 (Sigma, T9284-10L).
  • Tris-HCl pH 8.0, (IM Tris-HCl, pH 8.0 solution; Corning 46-031-CM)
  • GSH L-glutathione reduced, Sigma-Aldrich, G4251-100G
  • BGG 0.22 ⁇ M filtered, Sigma, G7516-25G
  • Triton X-100 Sigma, T9284-10L
  • Nanoliter quantities of 10-point, 3-fold serial dilution in DMSO were pre-dispensed into 1536 assay plates (Corning, #3724BC) for a final test concentration of 25 ⁇ M to 1.3 nM, top to lowest dose, respectively. Concentration and incubation times were optimized for the maximal signal-to-background while maintaining initial velocity conditions at a fixed substrate concentration.
  • the final concentration of USP30 human recombinant USP30, Boston Biochem, cat. #E-582
  • Final substrate (Ub-Rh110; Ubiquitin-Rhodamine 110, UbiQ-126) concentration was 25 nM with [Ub-Rh110] ⁇ Km.
  • 3 ⁇ L of 2 ⁇ USP30 was added to assay plates (pre-stamped with compound), preincubated for 30 minutes and then treated with 3 ⁇ L of 2 ⁇ Ub-Rh110. Plates were incubated for 30 minutes at room temperature before addition of 3 ⁇ L of stop solution (final concentration of 10 mM citric acid (Sigma, 251275-500G)). Fluorescence was read on the Envision (excitation at 485 nm and emission at 535 nm; Perkin Elmer) or on the PheraSTAR (excitation at 485 nm and emission at 535 nm; BMG Labtech) fluorescence reader.
  • IC 50 values were determined by curve fitting of the standard 4 parameter logistic fitting algorithm included in the Activity Base software package: IDBS XE Designer Model205. Data is fitted using the Levenburg Marquardt algorithm.
  • Cyanogen bromide (17.8 mg, 0.170 mmol) was added to a 0° C. mixture of 2-[5-(2-phenoxyphenyl)-1H-pyrazole-3-carbonyl]-2,6-diazabicyclo[3.2.1]octane 2,2,2-trifluoroacetate (80.0 mg, 0.170 mmol) and NaHCO 3 (82.0 mg, 0.957 mmol) in DMF (2 mL). The resulting mixture stirred for 16 h at 25° C. The reaction was quenched by the addition of water (10 mL). The resulting mixture was extracted with ethyl acetate (3 ⁇ 20 mL).
  • the compounds set forth in Table 4 were prepared by methods analogous to the preparation of compounds 1-a and 1-b. Each pair of compounds listed in Table 4 (i.e., compounds 2-a and 2-b, compounds 3-a and 3-b, etc.) was obtained as a racemic mixture, and were then separated by chiral HPLC according to the procedure described in Example 2, Step 7, to obtain the individual compounds in substantially enantiomerically pure form. The first and second eluting enantiomer of each enantiomer pair is identified in Table 4. The absolute stereochemistry of each enantiomer was arbitrarily assigned.
  • Cyanogen bromide (72.8 mg, 0.687 mmol) was added dropwise to a 0° C. solution of N-(3-azabicyclo[3.2.0]heptan-1-yl)-5-(2-phenoxyphenyl)-1H-pyrazole-3-carboxamide 2,2,2-trifluoroacetate (350 mg, 0.763 mmol) and sodium bicarbonate (785 mg, 9.25 mmol) in DMF (2 mL). The mixture was stirred for 1 h at 25° C. The solids were filtered out.
  • the filtrate was directly purified by Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 5 ⁇ m, 30 ⁇ 150 mm; Mobile phase, A: water (containing 0.05% ammonium hydrogen) and B: acetonitrile (35% B to 65% over 7 min); Detector: UV 220 and 254 nm) to afford N-(3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-5-(2-phenoxyphenyl)-1H-pyrazole-3-carboxamide as a white solid (70.0 mg).
  • Step 4 tert-butyl-(5-(2-phenoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxamido)-3-azabicyclo[3.1.0]hexane-3-carboxylate
  • Cyanogen bromide (58.5 mg, 0.552 mmol) was added dropwise to a 0° C. solution of N-(3-azabicyclo[3.1.0]hexan-1-yl)-5-(2-phenoxyphenyl)-1H-pyrazole-3-carboxamide 2,2,2-trifluoroacetate (280 mg, 0.613 mmol) and sodium bicarbonate (653 mg, 7.69 mmol) in DMF (2 mL). The mixture was stirred for 1 h at 25° C. The reaction was cooled to 0° C. and quenched with water (10 mL). The resulting mixture was extracted with ethyl acetate (3 ⁇ 10 mL).

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Abstract

The disclosure relates to USP30 Inhibitor Compounds, pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising same, and medical uses involving same.

Description

CROSS REFERENCE TO RELATED APPLICATIONS
The present application is a continuation of U.S. application Ser. No. 17/282,521, filed Apr. 2, 2021, which is a U.S. National Stage Application of PCT/US19/54803, filed Oct. 4, 2019, which claims priority to U.S. Provisional Patent Application No. 62/741,945, filed Oct. 5, 2018, the entire contents of each of which are hereby incorporated by reference.
TECHNICAL FIELD
This disclosure relates to inhibiting Ubiquitin-Specific Protease 30 (USP30), including novel compounds and methods for inhibiting USP30. The compounds and related methods are useful in the field of medicine including the development of new therapies (e.g., for the treatment of conditions related to the therapeutic inhibition of USP30 such as Parkinson's Disease (PD)).
BACKGROUND
The ubiquitination system is a highly regulated process which affects a wide variety of cellular activities and physiological processes. Ubiquitination is a reversible process, facilitated by a group of proteins known as deubiquitinating enzymes (DUBs), which deconjugate ubiquitin (Ub) from the substrate. DUBs are encoded by approximately 100 human genes and are divided into six families, with the largest family being the ubiquitin-specific proteases (USPs) with more than 50 members.
Ubiquitination regulates mitochondrial dynamics and biogenesis, affecting the abundance and function of these organelles. Mitochondria serve many functions to maintain cell health in mammals, including generating ATP. As mitochondria age they become damaged, losing their metabolic functionality, and begin releasing pro-apoptotic proteins. Mitochondria self-regulate their quality via the mechanism of mitophagy, which is the selective removal of damaged mitochondria from the cell. Ubiquitination of mitochondrial proteins is believed to contribute to mitochondrial dynamics in mammalian cells, possibly by “flagging” those proteins for inactivation. Ubiquitin-Specific Protease 30 (USP30) is embedded in the outer membrane of mitochondria, where it participates in the maintenance of mitochondrial morphology. It is believed that over-expression of USP30 can lead to a decrease in mitophagy.
Inactivating mutations in PINK1 and Parkin can impair mitophagy and result in accumulation of damaged mitochondria and neuronal toxicity, which has been implicated in Parkinson's Disease. USP30 opposes the ligase activity of Parkin and is a negative regulator of mitophagy. USP30 inhibition is expected to promote mitophagy and restore mitochondrial health.
SUMMARY
The disclosure provides compounds useful for inhibiting USP30, including USP30 Inhibitor Compounds as defined herein. In some embodiments, the disclosure provides a compound of formula (I):
Figure US11814386-20231114-C00001
or a pharmaceutically acceptable salt thereof, wherein
Ra, Rb, Rc, Rd, Re, Rf, Rg, and Rh are defined as follows:
    • (i) Ra and Rb form a C1-C4 alkylene group between the atoms to which they are attached, wherein said C1-C4 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Rc, Rd, Re, Rf, Rg, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
    • (ii) Ra and Re form a C1-C2 alkylene group between the atoms to which they are attached, wherein said C1-C2 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Rb, Rc, Rd, Rf, Rg, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
    • (iii) Ra and Rg form a C1-C3 alkylene group between the atoms to which they are attached, wherein said C1-C3 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Rb, Rc, Rd, Re, Rf, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
    • (iv) Rb and Re form a C1-C4 alkylene group between the atoms to which they are attached, wherein said C1-C4 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Ra, Rd, Re, Rf, Rg, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
    • (v) Rb and Re form a C1-C3 alkylene group between the atoms to which they are attached, wherein said C1-C3 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Ra, Rc, Rd, Rf, Rg, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
    • (vi) Rb and Rg form a C1-C4 alkylene group between the atoms to which they are attached, wherein said C1-C4 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Ra, Rc, Rd, Re, Rf, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
    • (vii) Re and Rd together with the atom to which they are attached, form a 3-6 membered cycloalkyl or heterocycloalkyl, wherein said 3-6 membered cycloalkyl or heterocycloalkyl is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Ra, Rb, Re, Rf, Rg, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
    • (viii) Re and Rd together form ═O; and Ra, Rb, Re, Rf, Rg, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
    • (ix) Rc and Re form a C1-C4 alkylene group between the atoms to which they are attached, wherein said C1-C4 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Ra, Rb, Rd, Rf, Rg, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
    • (x) Rc and Rg form a C1-C3 alkylene group between the atoms to which they are attached, wherein said C1-C3 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Ra, Rb, Rd, Re, Rf, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
    • (xi) Re and Rf together with the atom to which they are attached, form a 3-6 membered cycloalkyl or heterocycloalkyl, wherein said 3-6 membered cycloalkyl or heterocycloalkyl is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Ra, Rb, Rc, Rd, Rg, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
    • (xii) Re and Rf together form ═O; and Ra, Rb, Rc, Rd, Rg, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
    • (xiii) Re and Rg form a C1-C3 alkylene group between the atoms to which they are attached, wherein said C1-C3 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Ra, Rb, Rc, Rd, Rf, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
    • (xiv) Rg and Rh together with the atom to which they are attached, form a 3-6 membered cycloalkyl or heterocycloalkyl, wherein said 3-6 membered cycloalkyl or heterocycloalkyl is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Ra, Rb, Rc, Rd, Re, and Rf are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
    • (xv) Rg and Rh together form ═O; and Ra, Rb, Rc, Rd, Re, and Rf are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; and
    • Ar1 is phenylene or 5-6 membered heteroarylene, wherein said phenylene or heteroarylene is substituted with m R1 groups; and
    • Ar2 is phenylene or 5-10 membered heteroarylene, wherein said phenylene or heteroarylene is substituted with n R2 groups;
    • L is —O—, —S—, —NR3—, —C(R4)2—, —S(O)2—, or —S(O)—; M is C1-C6 alkyl, C1-C6 haloalkyl, 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein said cycloalkyl, phenyl, or heteroaryl is substituted with p R5 groups;
    • each occurrence of R1, R2, and R5 is independently halo, cyano, NO2, oxo, hydroxyl, —R6, —OR6, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, —C1-C6 alkylene-R6, C1-C6 alkoxy, C1-C6 haloalkoxy, —C0-C3 alkylene-NR6R7, —C0-C3 alkylene-NR7R8, —C0-C3 alkylene-C(O)NR6R7, —C0-C3 alkylene-C(O)NR7R8, —C0-C3 alkylene-NR7C(O)R6, —C0-C3 alkylene-NR7C(O)R6, —C0-C3 alkylene-NR7S(O)2R6, —C0-C3 alkylene-C(O)R6, —C0-C3 alkylene-C(O)R7, —C0-C3 alkylene-SR6, —C0-C3 alkylene-S(O)R6, —C0-C3 alkylene-S(O)2R6, —C0-C3 alkylene-S(O)2R7, —C0-C3 alkylene-S(O)2NR6R7, —C0-C3 alkylene-S(O)2NR7R8, —C0-C3 alkylene-NR7C(O)NR8R9, —C0-C3 alkylene-NR7S(O)2NR8R9, —C0-C3 alkylene-C(O)OR7, —C0-C3 alkylene-C(O)OR6, —C0-C3 alkylene-OC(O)R7, —C0-C3 alkylene-OC(O)R6, —C0-C3 alkylene-NR7C(O)OR8, or —C0-C3 alkylene-NR7S(O)2R8;
    • R3 is H, C1-C6 alkyl, or C1-C6 haloalkyl;
    • each R4 is independently H, C1-C6 alkyl, or C1-C6 haloalkyl, or two R4 groups together with the carbon atom to which they are attached form a 3-6 membered cycloalkyl or heterocycloalkyl;
    • each R6 is independently 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl, or 3-8 membered cycloalkyl, wherein said heteroaryl, heterocycloalkyl, aryl, or cycloalkyl is optionally substituted with 1-5 substituents independently selected from the group consisting of halo, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl, 3-8 membered cycloalkyl, —NR10C(O)NR11R12, —NR10R11, —C(O)R10, —NR10C(O)R11, —NR10C(O)OR11, —S(O)2R10, —C(O)NR10R11, —C(O)OR10, —S(O)2NR10R11, —NR10S(O)2R11, —OR10, —OC(O)R10, —OS(O)2R10, —OC(O)NR10R11, —OC(O)OR10, —OS(O)2NR10R11, —C(O)NR10C(O)NR11R12, —C(O)C(O)R10, —C(O)NR10C(O)R11, —C(O)NR10C(O)OR11, —C(O)S(O)2R10, —C(O)C(O)NR10R11, —C(O)C(O)OR10, —C(O)S(O)2NR10R11, —C(O)NR10S(O)2R11, —C1-C6 alkylene-R10, —C1-C6 alkylene-NR10C(O)NR11R12, —C1-C6 alkylene-NR10R11, —C1-C6 alkylene-C(O)R10, —C1-C6 alkylene-NR10C(O)R11, —C1-C6 alkylene-NR10C(O)OR11, —C1-C6 alkylene-S(O)2R10, —C1-C6 alkylene-C(O)NR10R11, —C1-C6 alkylene-C(O)OR10, —C1-C6 alkylene-S(O)2NR10R11, —C1-C6 alkylene-NR10S(O)2R11, —C1-C6 alkenylene-R10, —C1-C6 alkenylene-NR10C(O)NR11R12, —C1-C6 alkenylene-NR10R11, —C1-C6 alkenylene-C(O)R10, —C1-C6 alkenylene-NR10C(O)R11, —C1-C6 alkenylene-NR10C(O)OR11, —C1-C6 alkenylene-S(O)2R10, —C1-C6 alkenylene-C(O)NR10R11, —C1-C6 alkenylene-C(O)OR10, —C1-C6 alkenylene-S(O)2NR10R11, and —C1-C6 alkenylene-NR10S(O)2R11;
    • each R7, R8, and R9 is independently hydrogen or C1-C6 alkyl;
    • each R10, R11, and R12 is independently hydrogen, C1-C6 alkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl, or 3-8 membered cycloalkyl;
    • m is 0-4;
    • n is 0-4; and
    • p is 0-4.
In some embodiments, the disclosure provides a compound of formula (I-C):
Figure US11814386-20231114-C00002
or a pharmaceutically acceptable salt thereof, wherein R2, R5, n, p, Ra, Rb, Rc, Rd, Re, Rf, Rg, and Rh are all as defined for formula (I) above and described in classes and subclasses herein for formula (I), both singly and in combination.
In some embodiments, a USP30 Inhibitor Compound is a compound selected from the group consisting of:
Figure US11814386-20231114-C00003
wherein R2, R5, n, and p are as defined with respect to formula (I) herein, or a pharmaceutically acceptable salt thereof, having an IC50 value of about ≤1 μM (and preferably ≤0.5 μM or ≤0.1 μM) and >0.001 μM as measured in a Ubiquitin-Rhodamine 110 Assay as described in Example 1. In some embodiments, compounds of formula (I-C) are provided where R2 and R5 are both hydrogen.
In some embodiments, a USP30 Inhibitor Compound is a compound of the chemical formula:
Figure US11814386-20231114-C00004
wherein R2, R5, n, and p are as defined with respect to formula (I) herein, or a pharmaceutically acceptable salt thereof, having an IC50 value of about ≤1 μM (and preferably ≤0.5 μM or ≤0.1 μM) and >0.001 μM as measured in a Ubiquitin-Rhodamine 110 Assay as described in Example 1.
In some embodiments, a compound is any compound selected from the compounds listed in Table 1 herein.
DETAILED DESCRIPTION
The present disclosure relates to compounds of formula (I), as defined herein, pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising same, and medical uses involving same. In some embodiments, the compounds of formula (I) are USP30 Inhibitor Compounds. In other embodiments, the compounds of formula (I) are useful, for example, as analytical tools and/or control compounds in biological assays (e.g., compounds of any of the following aspects and embodiments that are not USP30 Inhibitor Compounds).
USP30 Inhibitor Compounds are useful in the development of new therapies for Parkinson's disease (PD), and in methods of treating diseases or conditions by inhibiting USP30 (such as PD). Parkin (E3 ubiquitin ligase) and PINK1 (kinase) are key regulators of mitophagy. In healthy mitochondria, PINK1 localization to the mitochondrial outer membrane (MOM) and exposure to the cytosol is limited by rapid import to the mitochondrial inner membrane (MIM). Once localized to the MIM, PINK1 is processed by several proteases, such as presenilin associated rhomboid-like protease (PARL), to yield a truncated version of PINK1 which is subsequently degraded by the proteasome (Meissner et al., Autophagy. 2015, 11(9), 1484-1498). Upon mitochondrial depolarization or dysfunction, PINK1 accumulates in the MOM, recruiting and activating Parkin via PINK1-dependent phosphorylation of both ubiquitin and Parkin. Consequently, activated Parkin ubiquitinates MOM proteins like TOMM20 to trigger mitophagy (Pickrell et al., Neuron. 2015, 85(2), 257-273). USP30 is embedded in the MOM with its catalytic DUB domain oriented towards the cytosol and has been shown to antagonize Parkin-mediated ubiquitination of common substrates, consequently opposing Parkin-mediated mitophagy. Genetic silencing of USP30 results in increased ubiquitination of several Parkin substrates followed by increased mitophagy. In model organisms, USP30 depletion is able to rescue mitophagy defects caused by pathogenic Parkin mutations, as well as restore mitochondria morphology and function, and dopamine levels. (Nakamura, et al., Mol Biol Cell. 2008, 19(5), 1903-1911; Bingol, et al., Nature 2014, 510(7505):370-5). Therefore, inhibition of USP30 with a compound disclosed herein could present a novel treatment paradigm for PD by promoting mitochondrial turnover.
Definitions
As used herein, the term “alkyl” means a substituted or unsubstituted hydrocarbon chain that is completely saturated, including straight-chain alkyl groups and branched-chain alkyl groups, and that has a single point of attachment to the rest of the molecule. In some embodiments, a straight chain or branched chain alkyl has about 1-20 carbon atoms in its backbone (e.g., C1-C20 for straight chain, C2-C20 for branched chain), and alternatively, about 1-10. In some embodiments, an alkyl has about 1-8 carbon atoms. In some embodiments, an alkyl has about 1-6 carbon atoms. In some embodiments, an alkyl has about 1-5 carbon atoms. In some embodiments, an alkyl has about 1-4 carbon atoms. In some embodiments, an alkyl has about 1-3 carbon atoms. In some embodiments, an alkyl has about 1-2 carbon atoms.
As used herein, the term “alkylene” refers to a bivalent alkyl group. Exemplary alkylenes include —CH2—, —CH2CH2—, —CH(CH3)—, —CH2CH(CH3)—, —CH(CH3)CH3)—, etc. In some embodiments, an “alkylene chain” is a polymethylene group, i.e., —(CH2)n—, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent.
As used herein, the term “alkenyl” refers to an alkyl group, as defined herein, having one or more double bonds.
As used herein, the term “alkenylene” refers to a bivalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent.
As used herein, the term “alkynyl” refers to an alkyl group, as defined herein, having one or more triple bonds.
The term “aryl” refers to ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term “aryl” may be used interchangeably with the term “aryl ring.” In certain embodiments of the present disclosure, “aryl” refers to an aromatic ring system and exemplary groups include phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.
The term “arylene” refers to a bivalent aryl group (e.g., phenylene).
As used herein, the term “cycloalkyl” refers to a cyclic alkyl group (e.g., a monocyclic alkyl group or a bicyclic alkyl group). In some embodiments, “cycloalkyl” refers to a monocyclic C3-C8 cycloalkyl group. In some embodiments, “cycloalkyl” refers to a monocyclic C3-C6 cycloalkyl group.
The terms “halogen” or “halo” mean F, Cl, Br, or I.
The term “heteroaryl” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14π electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms wherein the term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Exemplary heteroaryl groups include thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The term “heteroaryl”, as used herein, also includes groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Examplary groups include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. A heteroaryl group may be mono- or bicyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted.
The term “heteroarylene” refers to a bivalent heteroaryl group.
As used herein, the term “heterocycloalkyl” refers to a stable 3- to 7-membered monocyclic or 7- to 10-membered bicyclic cyclic moiety that is saturated and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms independently selected from nitrogen, oxygen, and sulfur, including any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. As an example, in a saturated ring having 1-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or +NR (as in N-substituted pyrrolidinyl). A heterocycloalkyl ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such heterocycloalkyl radicals include tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The term “heterocycloalkyl” also includes groups in which a heterocycloalkyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the heterocycloalkyl ring.
As used herein, a “USP30 Inhibitor Compound” refers to a compound having an IC50 of about 1 micromolar or less (i.e., an IC50 value of ≤1 μM and >0.001 μM) in the Ubiquitin-Rhodamine 110 Assay for USP30 as described in Example 1 herein. For example, a USP30 Inhibitor can be a compound of formula (I) having an IC50 value of ≤0.5 μM and >0.001 μM when tested in the Biochemical Assay of Example 1. In some embodiments, a USP30 Inhibitor is a compound of formula (I) having an IC50 value of ≤0.1 μM and >0.001 μM when tested in the Biochemical Assay of Example 1.
As used herein, the term “pharmaceutically acceptable salt” refers to salts of such compounds that are appropriate for use in pharmaceutical contexts, i.e., salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977).
Unless otherwise stated, all chemical structures and chemical names depicted herein without stereochemical descriptors shall be understood to include all stereoisomeric (e.g., enantiomeric or diastereomeric) forms of the compound depicted by the structure or name, as well as all geometric and conformational isomeric forms of the compound; for example, the R and S configurations for each stereocenter. Unless otherwise stated, such structures and names shall be understood to include a stereochemically pure form of the compound and any mixture of enantiomers, diastereomers, or geometric (or conformational) isomers. Unless otherwise stated, all tautomeric forms of the compounds of the disclosure are within the scope of the disclosure.
Unless otherwise stated, all chemical structures and chemical names depicted herein with stereochemical descriptors (i.e., hash and wedge bonds in the chemical structures; (R)- and (S)-designators in the chemical names) shall be understood to refer to a compound having the relative stereochemistry (but not necessarily the absolute stereochemistry) indicated by the stereochemical descriptors. Unless otherwise stated, such structures and names shall be understood to include an enantiomerically pure form of the compound having the relative stereochemistry indicated by the stereochemical descriptors or any mixture of enantiomers. In some embodiments, the enantiomers are present in a racemic mixture. In other embodiments, the enantiomer having the absolute stereochemistry suggested by the stereochemical descriptors is present in substantially enantiomerically pure form. In other embodiments, the enantiomer having the absolute stereochemistry opposite to that suggested by the stereochemical descriptors is present in substantially enantiomerically pure form.
Unless otherwise stated, all chemical structures and chemical names depicted herein with stereochemical descriptors (i.e., hash and wedge bonds in the chemical structures; (R)- and (S)-designators in the chemical names) and an “absolute” descriptor (“abs”) shall be understood to refer to a compound having the absolute stereochemistry indicated by the stereochemical descriptors. Unless otherwise stated, such structures and names shall be understood to include the compound in enantiomerically pure form or in a mixture with its enantiomer. In some embodiments, the enantiomers are present in a racemic mixture. In other embodiments, the enantiomer having the absolute stereochemistry indicated by the stereochemical descriptors is present in substantially enantiomerically pure form.
Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13C- or 14C-enriched carbon are within the scope of this disclosure.
It will be appreciated that throughout the present disclosure, unless otherwise indicated, reference to a compound of formula (I) is intended to also include formulas I-1, I-2, I-3, I-4, I-A, I-A-1, I-A-2, I-A-3, I-A-4, I-B, I-B-1, I-B-2, I-B-3, I-B-4, I-C, I-C-1, I-C-2, I-C-3, I-C-4, I-C-a, I-C-b, I-C-c, I-C-d, I-C-e, I-C-f, I-D, I-E, I-E-1, I-E-2, I-E-3, I-E-4, I-F-1, I-F-2, I-G-1, I-G-2, I-H-1, I-H-2, I-J-1, I-J-2, I-K-1, I-K-2, I-L-1, I-L-2, I-M, I-M-1, I-M-2, I-M-3, and I-M-4, and compound species of such formulas disclosed herein.
Compounds of the Disclosure
In one aspect, the disclosure relates to a compound of formula (I):
Figure US11814386-20231114-C00005
or a pharmaceutically acceptable salt thereof, wherein Ar1, Ar2, M, L, Ra, Rb, Rc, Rd, Re, Rf, Rg, and Rh are all as defined for formula (I) above.
In some embodiments, the present disclosure provides compounds, or pharmaceutically acceptable salts thereof, of formula (I-1):
Figure US11814386-20231114-C00006
  • wherein Ar1, Ar2, M, L, Ra, Rd, Re, Rf, Rg, and Rh are all as defined for formula (I) above and described in classes and subclasses herein for formula (I), both singly and in combination, and
  • wherein Rj, Rk, Rm, and Rn are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl.
In some embodiments, the present disclosure provides compounds, or pharmaceutically acceptable salts thereof, of formula (I-2):
Figure US11814386-20231114-C00007
  • wherein Ar1, Ar2, M, L, Ra, Rd, Re, Rf, Rg, and Rh are all as defined for formula (I) above and described in classes and subclasses herein for formula (I), both singly and in combination, and
  • wherein Rj and Rk are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl.
In some embodiments, the present disclosure provides compounds, or pharmaceutically acceptable salts thereof, of formula (I-3):
Figure US11814386-20231114-C00008
  • wherein Ar1, Ar2, M, L, Ra, Rd, Re, Rf, Rg, and Rh are all as defined for formula (I) above and described in classes and subclasses herein for formula (I), both singly and in combination, and
  • wherein Rj Rk, Rm, Rn, Ro, and Rp are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl.
In some embodiments, the present disclosure provides compounds, or pharmaceutically acceptable salts thereof, of formula (I-4):
Figure US11814386-20231114-C00009
  • wherein Ar1, Ar2, M, L, Ra, Rb, Rd, Rf, Rg, and Rh are all as defined for formula (I) above and described in classes and subclasses herein for formula (I), both singly and in combination, and
  • wherein Rq and Rr are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl.
In another aspect, the disclosure relates to a compound of formula (I-A):
Figure US11814386-20231114-C00010
or a pharmaceutically acceptable salt thereof, wherein:
    • X1 is C or N;
    • X2 is CH, CR1, O, S, N, NH, or NR1, as valency permits;
    • X3 is CH, CR1, O, S, N, NH, or NR1, as valency permits;
    • X4 is C or N;
    • X5 is a bond, CH, CR1, O, S, N, NH, or NR1, as valency permits;
    • X6 is CH, CR1, O, S, N, NH, or NR1, as valency permits;
    • Y1 is C or N;
    • Y2 is C or N;
    • Y3 is CH, CR2, O, S, N, NH, or NR2, as valency permits;
    • Y4 is a bond, CH, CR2, O, S, N, NH, or NR2, as valency permits;
    • Y5 is CH, CR2, O, S, N, NH, or NR2, as valency permits;
    • Y6 is CH, CR2, O, S, N, NH, or NR2, as valency permits,
    • provided that the ring comprising X1, X2, X3, X4, X5, and X6 is aromatic, and
    • that the ring comprising Y1, Y2, Y3, Y4, Y5, and Y6 is aromatic;
    • and wherein L, M, R1, R2, R5, Ra, Rb, Rc, Rd, Re, Rf, Rg, and Rh are all as defined for formula (I) above and described in classes and subclasses herein for formula (I), both singly and in combination.
In some embodiments, the present disclosure provides compounds, or pharmaceutically acceptable salts thereof, of formula (I-A-1):
Figure US11814386-20231114-C00011
  • wherein M, L, X1, X2, X3, X4, X5, X6, Y1, Y2, Y3, Y4, Y5, Y6, Ra, Rd, Re, Rf, Rg, and Rh are all as defined for formula (I-A) above and described in classes and subclasses herein for formula (I-A), both singly and in combination, and
  • wherein Rj, Rk, Rm, and Rn are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl.
In some embodiments, the present disclosure provides compounds, or pharmaceutically acceptable salts thereof, of formula (I-A-2):
Figure US11814386-20231114-C00012
  • wherein M, L, X1, X2, X3, X4, X5, X6, Y1, Y2, Y3, Y4, Y5, Y6, Ra, Rd, Re, Rf, Rg, and Rh are all as defined for formula (I-A) above and described in classes and subclasses herein for formula (I-A), both singly and in combination, and
  • wherein Rj and Rk are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl.
In some embodiments, the present disclosure provides compounds, or pharmaceutically acceptable salts thereof, of formula (I-A-3):
Figure US11814386-20231114-C00013
  • wherein M, L, X1, X2, X3, X4, X5, X6, Y1, Y2, Y3, Y4, Y5, Y6, Ra, Rd, Re, Rf, Rg, and Rh are all as defined for formula (I-A) above and described in classes and subclasses herein for formula (I-A), both singly and in combination, and
  • wherein Rj, Rk, Rm, Rn, Ro, and Rp are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl.
In some embodiments, the present disclosure provides compounds, or pharmaceutically acceptable salts thereof, of formula (I-A-4):
Figure US11814386-20231114-C00014
  • wherein M, L, X1, X2, X3, X4, X5, X6, Y1, Y2, Y3, Y4, Y5, Y6, Ra, Rb, Rd, Rf, Rg, and Rh are all as defined for formula (I-A) above and described in classes and subclasses herein for formula (I-A), both singly and in combination, and
  • wherein Rq and Rr are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl.
In another aspect, the disclosure relates to a compound of formula (I-B):
Figure US11814386-20231114-C00015
or a pharmaceutically acceptable salt thereof, wherein:
    • Y3 is CH, CR2, or N;
    • Y4 is CH, CR2, or N;
    • Y5 is CH, CR2, or N;
    • Y6 is CH, CR2, or N; and
    • wherein X1, X2, X3, X4, X6, L, M, Ra, Rb, Rc, Rd, Re, Rf, Rg, and Rh are all as defined for formula (I) above and described in classes and subclasses herein for formula (I-A), both singly and in combination.
In some embodiments, the present disclosure provides compounds, or pharmaceutically acceptable salts thereof, of formula (I-B-1):
Figure US11814386-20231114-C00016
  • wherein M, L, X1, X2, X3, X4, X6, Y3, Y4, Y5, Y6, Ra, Rd, Re, Rf, Rg, and Rh are all as defined for formula (I-B) above and described in classes and subclasses herein for formula (I-B), both singly and in combination, and
  • wherein Rj, Rk, Rm, and Rn are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl.
In some embodiments, the present disclosure provides compounds, or pharmaceutically acceptable salts thereof, of formula (I-B-2):
Figure US11814386-20231114-C00017
  • wherein M, L, X1, X2, X3, X4, X6, Y3, Y4, Y5, Y6, Ra, Rd, Re, Rf, Rg, and Rh are all as defined for formula (I-B) above and described in classes and subclasses herein for formula (I-B), both singly and in combination, and
  • wherein Rj and Rk are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl.
In some embodiments, the present disclosure provides compounds, or pharmaceutically acceptable salts thereof, of formula (I-B-3):
Figure US11814386-20231114-C00018
  • wherein M, L, X1, X2, X3, X4, X6, Y3, Y4, Y5, Y6, Ra, Rd, Re, Rf, Rg, and Rh are all as defined for formula (I-B) above and described in classes and subclasses herein for formula (I-B), both singly and in combination, and
  • wherein Rj, Rk, Rm, Rn, Ro, and Rp are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl.
In some embodiments, the present disclosure provides compounds, or pharmaceutically acceptable salts thereof, of formula (I-B-4):
Figure US11814386-20231114-C00019
  • wherein M, L, X1, X2, X3, X4, X6, Y3, Y4, Y5, Y6, Ra, Rd, Re, Rf, Rg, and Rh are all as defined for formula (I-B) above and described in classes and subclasses herein for formula (I-B), both singly and in combination, and
  • wherein Rq and Rr are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl.
In another aspect, the disclosure relates to a compound of formula (I-C):
Figure US11814386-20231114-C00020
or a pharmaceutically acceptable salt thereof, wherein R2, R3, n, p, Ra, Rb, Rc, Rd, Re, Rf, Rg and Rh are all as defined for formula (I) above and described in classes and subclasses herein for formula (I), both singly and in combination.
In some embodiments, the present disclosure provides compounds, or pharmaceutically acceptable salts thereof, of formula (I-C-1):
Figure US11814386-20231114-C00021
  • wherein R2, R5, n, p, Ra, Rd, Re, Rf, Rg, and Rh are all as defined for formula (I-C) above and described in classes and subclasses herein for formula (I-C), both singly and in combination, and
  • wherein Rj, Rk, Rm, and Rn are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl.
In some embodiments, the present disclosure provides compounds, or pharmaceutically acceptable salts thereof, of formula (I-C-2):
Figure US11814386-20231114-C00022
  • wherein R2, R5, n, p, Ra, Rd, Re, Rf, Rg, and Rh are all as defined for formula (I-C) above and described in classes and subclasses herein for formula (I-C), both singly and in combination, and
  • wherein Rj and Rk are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl.
In some embodiments, the present disclosure provides compounds, or pharmaceutically acceptable salts thereof, of formula (I-C-3):
Figure US11814386-20231114-C00023
  • wherein R2, R5, n, p, Ra, Rd, Re, Rf, Rg, and Rh are all as defined for formula (I-C) above and described in classes and subclasses herein for formula (I-C), both singly and in combination, and
  • wherein Rj, Rk, Rm, Rn, Ro, and Rp are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl.
In some embodiments, the present disclosure provides compounds, or pharmaceutically acceptable salts thereof, of formula (I-C-4):
Figure US11814386-20231114-C00024
  • wherein R2, R5, n, p, Ra, Rb, Rd, Rf, Rg, and Rh are all as defined for formula (I-C) above and described in classes and subclasses herein for formula (I-C), both singly and in combination, and
  • wherein Rq and Rr are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl.
In some embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (I-C-a):
Figure US11814386-20231114-C00025
wherein R2, R5, n, and p are all as defined for formula (I-C) above and described in classes and subclasses herein for formula (I-C), both singly and in combination.
In some embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (I-C-b):
Figure US11814386-20231114-C00026
wherein R2, R5, n, and p are all as defined for formula (I-C) above and described in classes and subclasses herein for formula (I-C), both singly and in combination.
In some embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (I-C-c):
Figure US11814386-20231114-C00027
wherein R2, R5, n, and p are all as defined for formula (I-C) above and described in classes and subclasses herein for formula (I-C), both singly and in combination.
In some embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (I-C-d):
Figure US11814386-20231114-C00028
wherein R2, R5, n, and p are all as defined for formula (I-C) above and described in classes and subclasses herein for formula (I-C), both singly and in combination.
In some embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (I-C-e):
Figure US11814386-20231114-C00029
wherein R2, R5, n, and p are all as defined for formula (I-C) above and described in classes and subclasses herein for formula (I-C), both singly and in combination.
In some embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (I-C-f):
Figure US11814386-20231114-C00030
wherein R2, R5, n, and p are all as defined for formula (I-C) above and described in classes and subclasses herein for formula (I-C), both singly and in combination.
In another aspect, the disclosure relates to a compound of formula (I-D):
Figure US11814386-20231114-C00031
or a pharmaceutically acceptable salt thereof, wherein Ra, Rb, Rc, Rd, Re, Rf, Rg and Rh are all as defined for formula (I) above and described in classes and subclasses herein for formula (I), both singly and in combination.
In another aspect, the disclosure relates to a compound of formula (I-E):
Figure US11814386-20231114-C00032
or a pharmaceutically acceptable salt thereof, wherein Ra, Rb, Rc, Rd, Re, Rf, and Rg are all as defined for formula (I) above and described in classes and subclasses herein for formula (I), both singly and in combination. In some embodiments, the present disclosure provides compounds, or pharmaceutically acceptable salts thereof, of formula (I-E-1):
Figure US11814386-20231114-C00033
In some embodiments, the compound of formula (I-E-1) has the absolute stereochemistry of the first eluting isomer when a racemic mixture of the compound of formula (I-E-1) is separated by the procedure described in Example 3, Step 6. In some embodiments, the compound of formula (I-E-1) has the absolute stereochemistry of the second eluting isomer when a racemic mixture of the compound of formula (I-E-1) is separated by the procedure described in Example 3, Step 6.
In some embodiments, the compound of formula (I-E-1) is:
Figure US11814386-20231114-C00034
In some embodiments, the compound of formula (I-E-1) is:
Figure US11814386-20231114-C00035
In some embodiments, the present disclosure provides compounds, or pharmaceutically acceptable salts thereof, of formula (I-E-2):
Figure US11814386-20231114-C00036
In some embodiments, the compound of formula (I-E-2) has the absolute stereochemistry of the first eluting isomer when a racemic mixture of the compound of formula (I-E-2) is separated by the procedure described in Example 4, Step 6. In some embodiments, the compound of formula (I-E-2) has the absolute stereochemistry of the second eluting isomer when a racemic mixture of the compound of formula (I-E-2) is separated by the procedure described in Example 4, Step 6.
In some embodiments, the compound of formula (I-E-2) is:
Figure US11814386-20231114-C00037
In some embodiments, the compound of formula (I-E-2) is:
Figure US11814386-20231114-C00038
In some embodiments, the present disclosure provides compounds, or pharmaceutically acceptable salts thereof, of formula (I-E-3):
Figure US11814386-20231114-C00039
In some embodiments, the compound of formula (I-E-3) has the absolute stereochemistry of the first eluting isomer when a racemic mixture of the compound of formula (I-E-3) is separated by the procedure described in Example 2, Step 7. In some embodiments, the compound of formula (I-E-3) has the absolute stereochemistry of the second eluting isomer when a racemic mixture of the compound of formula (I-E-3) is separated by the procedure described in Example 2, Step 7.
In some embodiments, the compound of formula (I-E-3) is:
Figure US11814386-20231114-C00040
In some embodiments, the compound of formula (I-E-3) is:
Figure US11814386-20231114-C00041
In some embodiments, the present disclosure provides compounds, or pharmaceutically acceptable salts thereof, of formula (I-E-4):
Figure US11814386-20231114-C00042
In some embodiments, the compound of formula (I-E-4) has the absolute stereochemistry of the first eluting isomer when a racemic mixture of the compound of formula (I-E-4) is separated by the procedure described in Example 2, Step 7. In some embodiments, the compound of formula (I-E-4) has the absolute stereochemistry of the second eluting isomer when a racemic mixture of the compound of formula (I-E-4) is separated by the procedure described in Example 2, Step 7.
In some embodiments, the compound of formula (I-E-4) is:
Figure US11814386-20231114-C00043
In some embodiments, the compound of formula (I-E-4) is:
Figure US11814386-20231114-C00044
In another aspect, the disclosure relates to a compound of formula (I-F-1) or (I-F-2):
Figure US11814386-20231114-C00045
or a pharmaceutically acceptable salt thereof, wherein X1, X2, X3, X4, X5, X6, Y1, Y2, Y3, Y4, Y5, Y6, L, and M are all as defined for formula (I-A) above and described in classes and subclasses herein for formula (I-A), both singly and in combination.
In some embodiments, the compounds of formula (I-F-1) and (I-F-2) are present in a racemic mixture. In other embodiments, the compound of formula (I-F-1) or (J-F-2) is present in substantially enantiomerically pure form. The compounds of formula (I-F-1) and (I-F-2) can be separated from one another by chiral HPLC, such as by the procedure described in Example 2, Step 7 or Example 3, Step 6.
In another aspect, the disclosure relates to a compound of formula (I-G-1) or (I-G-2):
Figure US11814386-20231114-C00046
or a pharmaceutically acceptable salt thereof, wherein X1, X2, X3, X4, X5, X6, Y1, Y2, Y3, Y4, Y5, Y6, L, and M are all as defined for formula (I-A) above and described in classes and subclasses herein for formula (I-A), both singly and in combination.
In some embodiments, the compounds of formula (I-G-1) and (I-G-2) are present in a racemic mixture. In other embodiments, the compound of formula (I-G-1) or (I-G-2) is present in substantially enantiomerically pure form. The compounds of formula (I-G-1) and (I-G-2) can be separated from one another by chiral HPLC, such as by the procedure described in Example 2, Step 7, or Example 4, Step 6.
In another aspect, the disclosure relates to a compound of formula (I-H-1) or (I-H-2):
Figure US11814386-20231114-C00047
or a pharmaceutically acceptable salt thereof, wherein X1, X2, X3, X4, X5, X6, Y1, Y2, Y3, Y4, Y5, Y6, L, and M are all as defined for formula (I-A) above and described in classes and subclasses herein for formula (I-A), both singly and in combination.
In some embodiments, the compounds of formula (I-H-1) and (I-H-2) are present in a racemic mixture. In other embodiments, the compound of formula (I-H-1) or (I-H-2) is present in substantially enantiomerically pure form. The compounds of formula (I-H-1) and (I-H-2) can be separated from one another by chiral HPLC, such as by the procedure described in Example 2, Step 7.
In another aspect, the disclosure relates to a compound of formula (I-J-1) or (I-J-2):
Figure US11814386-20231114-C00048
or a pharmaceutically acceptable salt thereof, wherein X1, X2, X3, X4, X5, X6, Y1, Y2, Y3, Y4, Y5, Y6, L, and M are all as defined for formula (I-A) above and described in classes and subclasses herein for formula (I-A), both singly and in combination.
In some embodiments, the compounds of formula (I-J-1) and (I-J-2) are present in a racemic mixture. In other embodiments, the compound of formula (I-J-1) or (I-J-2) is present in substantially enantiomerically pure form. The compounds of formula (I-J-1) and (I-J-2) can be separated from one another by chiral HPLC, such as by the procedure described in Example 2, Step 7.
In some embodiments, the present disclosure provides compounds, or pharmaceutically acceptable salts thereof, of formula (I-K-1) or (I-K-2):
Figure US11814386-20231114-C00049
wherein M, L, X1, X2, X3, X4, X5, X6, Y1, Y2, Y3, Y4, Y5, and Y6 are all as defined for formula (I-A) above and described in classes and subclasses herein for formula (I-A), both singly and in combination.
In some embodiments, the present disclosure provides compounds, or pharmaceutically acceptable salts thereof, of formula (I-L-1) or (I-L-2):
Figure US11814386-20231114-C00050
wherein M, L, X1, X2, X3, X4, X5, X6, Y1, Y2, Y3, Y4, Y5, and Y6 are all as defined for formula (I-A) above and described in classes and subclasses herein for formula (I-A), both singly and in combination.
In some embodiments, the present disclosure provides compounds, or pharmaceutically acceptable salts thereof, of formula (I-M):
Figure US11814386-20231114-C00051
wherein M, L, X1, X2, X3, X4, X5, X6, Ra, Rb, Rc, Rd, Re, Rf, Rg, and Rh are all as defined for formula (I) and (I-A) above and described in classes and subclasses herein for formula (I) and (I-A), both singly and in combination.
In some embodiments, the present disclosure provides compounds, or pharmaceutically acceptable salts thereof, of formula (I-M-1):
Figure US11814386-20231114-C00052
  • wherein M, L, X1, X2, X3, X4, X5, X6, Ra, Rd, Re, Rf, Rg, and Rh are all as defined for formula (I-M) above and described in classes and subclasses herein for formula (I-M), both singly and in combination, and
  • wherein Rj, Rk, Rm, and Rn are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl.
In some embodiments, the present disclosure provides compounds, or pharmaceutically acceptable salts thereof, of formula (I-M-2):
Figure US11814386-20231114-C00053
  • wherein M, L, X1, X2, X3, X4, X5, X6, Ra, Rd, Re, Rf, Rg, and Rh are all as defined for formula (I-M) above and described in classes and subclasses herein for formula (I-M), both singly and in combination, and
  • wherein Rj and Rk are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl.
In some embodiments, the present disclosure provides compounds, or pharmaceutically acceptable salts thereof, of formula (I-M-3):
Figure US11814386-20231114-C00054
  • wherein M, L, X1, X2, X3, X4, X5, X6, Ra, Rd, Re, Rf, Rg, and Rh are all as defined for formula (I-M) above and described in classes and subclasses herein for formula (I-M), both singly and in combination, and
  • wherein Rj, Rk, Rm, Rn, Ro, and Rp are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl.
In some embodiments, the present disclosure provides compounds, or pharmaceutically acceptable salts thereof, of formula (I-M-4):
Figure US11814386-20231114-C00055
  • wherein M, L, X1, X2, X3, X4, X5, X6, Ra, Rb, Rd, Rf, Rg, and Rh are all as defined for formula (I-M) above and described in classes and subclasses herein for formula (I-M), both singly and in combination, and
  • wherein Rq and Rr are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl.
In some embodiments, the disclosure relates to a compound of formula (I), (I-1), (I-2), (I-3), or (I-4), or a pharmaceutically acceptable salt thereof, wherein Ar1 is independently phenylene or 5-6 membered heteroarylene, wherein said phenylene or heteroarylene is substituted with m R1 groups. In some embodiments, Ar1 is phenylene substituted with m R1 groups. In some embodiments, Ar1 is phenylene substituted with 1-2 R1 groups selected from the group consisting of halo, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 hydroxyalkyl. In some embodiments, Ar1 is phenylene. In some embodiments, Ar1 is 5-6 membered heteroarylene substituted with m R1 groups. In some embodiments, Ar1 is 5-6 membered heteroarylene substituted with 1-2 R1 groups selected from the group consisting of halo, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 hydroxyalkyl. In some embodiments, Ar1 is 5-membered heteroarylene substituted with m R1 groups. In some embodiments, Ar1 is pyrazole. In some embodiments, Ar1 is thiazole. In some embodiments, Ar1 is 6-membered heteroarylene substituted with m R1 groups.
In some embodiments, the disclosure relates to a compound of formula (I), (I-1), (I-2), (I-3), (1-4), (I-M), (I-M-1), (I-M-2), (I-M-3), or (I-M-4), or a pharmaceutically acceptable salt thereof, wherein Ar2 is independently phenylene or 5-10 membered heteroarylene, wherein said phenylene or heteroarylene is substituted with n R2 groups. In some embodiments, Ar2 is phenylene or 5-6 membered heteroarylene, wherein said phenylene or heteroarylene is substituted with n R2 groups. In some embodiments, Ar2 is phenylene substituted with n R2 groups. In some embodiments, Ar2 is phenylene substituted with 1-2 R2 groups selected from the group consisting of halo, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 hydroxyalkyl. In some embodiments, Ar2 is phenylene. In some embodiments, Ar2 is 5-10 membered heteroarylene substituted with n R2 groups. In some embodiments, Ar2 is 5-6 membered heteroarylene substituted with 1-2 R2 groups selected from the group consisting of halo, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 hydroxyalkyl. In some embodiments, Ar2 is 5-membered heteroarylene substituted with n R2 groups. In some embodiments, Ar2 is 6-membered heteroarylene substituted with n R2 groups. In some embodiments, Ar2 is pyridine. In some embodiments, Ar2 is 7-membered heteroarylene substituted with n R2 groups. In some embodiments, Ar2 is 8-membered heteroarylene substituted with n R2 groups. In some embodiments, Ar2 is 9-membered heteroarylene substituted with n R2 groups. In some embodiments, Ar2 is 10-membered heteroarylene substituted with n R2 groups.
In some embodiments, the disclosure relates to a compound of formula (I), (I-1), (I-2), (I-3), (I-4), (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-B), (I-B-1), (I-B-2), (I-B-3), (I-B-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), (I-L-2), (I-M), (I-M-1), (I-M-2), (I-M-3), or (I-M-4), or a pharmaceutically acceptable salt thereof, wherein L is —O—, —S—, —NR3—, —C(R4)2—, —S(O)2—, or —S(O)—. In some embodiments, L is —O—, —S—, or —NH—. In some embodiments, L is —O—. In some embodiments, L is —S—. In some embodiments, L is —NR3—. In some embodiments, L is —NH—. In some embodiments, L is —C(R4)2—. In some embodiments, L is —CH2—. In some embodiments, L is —S(O)2—. In some embodiments, L is —S(O)—.
In some embodiments, the disclosure relates to a compound of formula (I), (I-1), (I-2), (I-3), (I-4), (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-B), (I-B-1), (I-B-2), (I-B-3), (I-B-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), (I-L-2), (I-M), (I-M-1), (I-M-2), (I-M-3), or (I-M-4), or a pharmaceutically acceptable salt thereof, wherein M is C1-C6 alkyl, C1-C6 haloalkyl, 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein said cycloalkyl, phenyl, or heteroaryl is substituted with p R5 groups. In some embodiments, M is 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein said cycloalkyl, phenyl, or heteroaryl is substituted with p R5 groups. In some embodiments, M is C1-C6 alkyl. In some embodiments, M is C1-C6 haloalkyl. In some embodiments, M is 3-6 membered cycloalkyl substituted with p R5 groups. In some embodiments, M is 3-6 membered cycloalkyl. In some embodiments, M is 3-6 membered cycloalkyl substituted with 1-2 R5 groups selected from the group consisting of halo, cyano, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 hydroxyalkyl. In some embodiments, M is phenyl substituted with p R5 groups. In some embodiments, M is phenyl. In some embodiments, M is phenyl substituted with 1-2 R5 groups selected from the group consisting of halo, cyano, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 hydroxyalkyl. In some embodiments, M is phenyl substituted with fluoro. In some embodiments, M is 5-6 membered heteroaryl substituted with p R5 groups. In some embodiments, M is 5-6 membered heteroaryl. In some embodiments, M is 5-6 membered heteroaryl substituted with 1-2 R5 groups selected from the group consisting of halo, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 hydroxyalkyl.
In some embodiments, the disclosure relates to a compound of formula (I), (I-1), (I-2), (I-3), (I-4), (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-B), (I-B-1), (I-B-2), (I-B-3), (I-B-4), (I-C), (I-C-1), (I-C-2), (I-C-3), (I-C-4), (I-C-a), (I-C-b), (I-C-c), (I-C-d), (I-C-e), (I-C-f), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), (I-L-2), (I-M), (I-M-1), (I-M-2), (I-M-3), or (I-M-4), or a pharmaceutically acceptable salt thereof, wherein each occurrence of R1, R2, and R5 is independently halo, cyano, NO2, oxo, hydroxyl, —R6, —OR6, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, —C1-C6 alkylene-R6, C1-C6 alkoxy, C1-C6 haloalkoxy, —C0-C3 alkylene-NR6R7, —C0-C3 alkylene-NR7R8, —C0-C3 alkylene-C(O)NR6R7, —C0-C3 alkylene-C(O)NR7R8, —C0-C3 alkylene-NRC(O)R6, —C0-C3 alkylene-NR7C(O)R8, —C0-C3 alkylene-NR7S(O)2R6, —C0-C3 alkylene-C(O)R6, —C0-C3 alkylene-C(O)R7, —C0-C3 alkylene-SR6, —C0-C3 alkylene-S(O)R6, —C0-C3 alkylene-S(O)2R6, —C0-C3 alkylene-S(O)2R7, —C0-C3 alkylene-S(O)2NR6R7, —C0-C3 alkylene-S(O)2NR7R8, —C0-C3 alkylene-NR7C(O)NR8R9, —C0-C3 alkylene-NR7S(O)2NR8R9, —C0-C3 alkylene-C(O)OR7, —C0-C3 alkylene-C(O)OR6, —C0-C3 alkylene-OC(O)R7, —C0-C3 alkylene-OC(O)R6, —C0-C3 alkylene-NR7C(O)OR8, or —C0-C3 alkylene-NR7S(O)2R8. In some embodiments, each occurrence of R1 is independently halo, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 hydroxyalkyl. In some embodiments, each occurrence of R1 is independently halo (e.g., fluoro, chloro, bromo, or iodo). In some embodiments, each occurrence of R1 is fluoro. In some embodiments, each occurrence of R1 is cyano. In some embodiments, each occurrence of R1 is hydroxyl. In some embodiments, each occurrence of R1 is C1-C6 alkyl. In some embodiments, each occurrence of R1 is C1-C6 alkoxy. In some embodiments, each occurrence of R1 is C1-C6 haloalkyl. In some embodiments, each occurrence of R1 is C1-C6 hydroxyalkyl. In some embodiments, each occurrence of R2 is independently halo, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 hydroxyalkyl. In some embodiments, each occurrence of R2 is independently halo (e.g., fluoro, chloro, bromo, or iodo). In some embodiments, each occurrence of R2 is fluoro. In some embodiments, each occurrence of R2 is cyano. In some embodiments, each occurrence of R2 is hydroxyl. In some embodiments, each occurrence of R2 is C1-C6 alkyl. In some embodiments, each occurrence of R2 is C1-C6 alkoxy. In some embodiments, each occurrence of R2 is C1-C6 haloalkyl. In some embodiments, each occurrence of R2 is C1-C6 hydroxyalkyl. In some embodiments, each occurrence of R5 is independently halo, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 hydroxyalkyl. In some embodiments, each occurrence of R5 is independently halo (e.g., fluoro, chloro, bromo, or iodo). In some embodiments, each occurrence of R5 is fluoro. In some embodiments, each occurrence of R5 is cyano. In some embodiments, each occurrence of R5 is hydroxyl. In some embodiments, each occurrence of R5 is C1-C6 alkyl. In some embodiments, each occurrence of R5 is C1-C6 alkoxy. In some embodiments, each occurrence of R5 is C1-C6 haloalkyl. In some embodiments, each occurrence of R5 is C1-C6 hydroxyalkyl.
In some embodiments, the disclosure relates to a compound of formula (I), (I-1), (I-2), (I-3), (I-4), (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-B), (I-B-1), (I-B-2), (I-B-3), (I-B-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), (I-L-2), (I-M), (I-M-1), (I-M-2), (I-M-3), or (I-M-4), or a pharmaceutically acceptable salt thereof, wherein R3 is H, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, R3 is H. In some embodiments, R3 is C1-C6 alkyl. In some embodiments, R3 is C1-C6 haloalkyl.
In some embodiments, the disclosure relates to a compound of formula (I), (I-1), (I-2), (I-3), (I-4), (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-B), (I-B-1), (I-B-2), (I-B-3), (I-B-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), (I-L-2), (I-M), (I-M-1), (I-M-2), (I-M-3), or (I-M-4), or a pharmaceutically acceptable salt thereof, wherein each R4 is independently H, C1-C6 alkyl, or C1-C6 haloalkyl, or two R4 groups together with the carbon atom to which they are attached form a 3-6 membered cycloalkyl or heterocycloalkyl. In some embodiments, each R4 is H. In some embodiments, two R4 groups together with the carbon atom to which they are attached form a 3-6 membered cycloalkyl. In some embodiments, two R4 groups together with the carbon atom to which they are attached form a 3-6 membered heterocycloalkyl.
In some embodiments, the disclosure relates to a compound of formula (I), (I-1), (I-2), (I-3), (I-4), (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-B), (I-B-1), (I-B-2), (I-B-3), (I-B-4), (I-C), (I-C-1), (I-C-2), (I-C-3), (I-C-4), (I-C-a), (I-C-b), (I-C-c), (I-C-d), (I-C-e), (I-C-f), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), (I-L-2), (I-M), (I-M-1), (I-M-2), (I-M-3), or (I-M-4), or a pharmaceutically acceptable salt thereof, wherein each R6 is 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl, or 3-8 membered cycloalkyl, wherein said heteroaryl, heterocycloalkyl, aryl, or cycloalkyl is optionally substituted with 1-5 substituents independently selected from the group consisting of halo, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl, 3-8 membered cycloalkyl, —NR10C(O)NR11R12, —NR10R11, —C(O)R10, —NR10C(O)R11, —NR10C(O)OR11, —S(O)2R10, —C(O)NR10R11, —C(O)OR10, —S(O)2NR10R11, —NR10S(O)2R11, —OR10, —OC(O)R10, —OS(O)2R10, —OC(O)NR10R11, —OC(O)OR10, —OS(O)2NR10R11, —C(O)NR10C(O)NR11R12, —C(O)C(O)R10, —C(O)NR10C(O)R1, —C(O)NR10C(O)OR11, —C(O)S(O)2R10, —C(O)C(O)NR10R11, —C(O)C(O)OR10, —C(O)S(O)2NR10R11, —C(O)NR10S(O)2R11, —C1-C6 alkylene-R10, —C1-C6 alkylene-NR10C(O)NR11R12, —C1-C6 alkylene-NR10R11, —C1-C6 alkylene-C(O)R10, —C1-C6 alkylene-NR10C(O)R11, —C1-C6 alkylene-NR10C(O)OR11, —C1-C6 alkylene-S(O)2R10, —C1-C6 alkylene-C(O)NR10R11, —C1-C6 alkylene-C(O)OR10, —C1-C6 alkylene-S(O)2NR10R11, —C1-C6 alkylene-NR10S(O)2R11, —C1-C6 alkenylene-R10, —C1-C6 alkenylene-NR10C(O)NR11R12, —C1-C6 alkenylene-NR10R11, —C1-C6 alkenylene-C(O)R10, —C1-C6 alkenylene-NR10C(O)R11, —C1-C6 alkenylene-NR10C(O)OR11, —C1-C6 alkenylene-S(O)2R10, —C1-C6 alkenylene-C(O)NR10R11, —C1-C6 alkenylene-C(O)OR10, —C1-C6 alkenylene-S(O)2NR10R11, and —C1-C6 alkenylene-NR10S(O)2R11. In some embodiments, each R6 is independently optionally substituted 5-10 membered heteroaryl. In some embodiments, each R6 is independently optionally substituted 4-10 membered heterocycloalkyl. In some embodiments, each R6 is independently optionally substituted 6-10 membered aryl. In some embodiments, each R6 is independently optionally substituted 3-8 membered cycloalkyl.
In some embodiments, the disclosure relates to a compound of formula (I), (I-1), (I-2), (I-3), (I-4), (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-B), (I-B-1), (I-B-2), (I-B-3), (I-B-4), (I-C), (I-C-1), (I-C-2), (I-C-3), (I-C-4), (I-C-a), (I-C-b), (I-C-c), (I-C-d), (I-C-e), (I-C-f), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), (I-L-2), (I-M), (I. M-1), (I-M-2), (I-M-3), or (I-M-4), or a pharmaceutically acceptable salt thereof, wherein each R7, R8, and R9 is independently hydrogen or C1-C6 alkyl. In some embodiments, each R7, R8, and R9 is independently hydrogen.
In some embodiments, the disclosure relates to a compound of formula (I), (I-1), (I-2), (I-3), (I-4), (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-B), (I-B-1), (I-B-2), (I-B-3), (I-B-4), (I. C), (I-C-1), (I-C-2), (I-C-3), (I-C-4), (I-C-a), (I-C-b), (I-C-c), (I-C-d), (I-C-e), (I-C-f), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), (I-L-2), (I-M), (I. M-1), (I-M-2), (I-M-3), or (I-M-4), or a pharmaceutically acceptable salt thereof, wherein each R10, R11, and R12 is independently hydrogen, C1-C6 alkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl, or 3-8 membered cycloalkyl. In some embodiments, each R10, R11, and R12 is independently hydrogen.
In some embodiments, the disclosure relates to a compound of formula (I), (I-1), (I-2), (1-3), or (1-4), or a pharmaceutically acceptable salt thereof, wherein m is 0-4 (i.e., m is 0, 1, 2, 3, or 4). In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 1 or 2.
In some embodiments, the disclosure relates to a compound of formula (I), (I-1), (I-2), (I-3), (I-4), (I-C), (I-C-1), (I-C-2), (I-C-3), (I-C-4), (I-C-a), (I-C-b), (I-C-c), (I-C-d), (I-C-e), (I-C-f), (I-M), (I-M-1), (I-M-2), (I-M-3), or (I-M-4), or a pharmaceutically acceptable salt thereof, wherein n is 0-4 (i.e., n is 0, 1, 2, 3, or 4). In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 1 or 2.
In some embodiments, the disclosure relates to a compound of formula (I), (I-1), (I-2), (I-3), (I-4), (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-B), (I-B-1), (I-B-2), (I-B-3), (I-B-4), (I-C), (I-C-1), (I-C-2), (I-C-3), (I-C-4), (I-C-a), (I-C-b), (I-C-c), (I-C-d), (I-C-e), (I-C-f), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), (I-L-2), (I-M), (I-M-1), (I-M-2), (I-M-3), or (I-M-4), or a pharmaceutically acceptable salt thereof, wherein p is 0-4 (i.e., p is 0, 1, 2, 3, or 4). In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 0, 1, or 2. In some embodiments, p is 1 or 2. In some embodiments, n and p are both 0. In some embodiments, m and n are both 0. In some embodiments, m and n are both 0. In some embodiments, m, n, and p are 0. In some embodiments, m and n are 0, and p is 1.
In some embodiments, the disclosure relates to a compound of formula (I), (I-A), (I-B), (I-C), (I-D), (I-E), or (I-M), or a pharmaceutically acceptable salt thereof, wherein Ra and Rb form a C1-C4 alkylene group between the atoms to which they are attached, wherein said C1-C4 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl. In some embodiments, Ra and Rb form a C1-C4 alkylene group between the atoms to which they are attached; and Rc, Rd, Re, Rf, Rg, and Rh are each hydrogen. In some embodiments, Ra and Rb form a C1 alkylene group between the atoms to which they are attached; and Rc, Rd, Re, Rf, Rg, and Rh are each hydrogen. In some embodiments, Ra and Rb form a C2 alkylene group between the atoms to which they are attached; and Rc, Rd, Re, Rf, Rg, and Rh are each hydrogen. In some embodiments, Ra and Rb form a C3 alkylene group between the atoms to which they are attached; and Rc, Rd, Re, Rf, Rg, and Rh are each hydrogen. In some embodiments, Ra and Rb form a C4 alkylene group between the atoms to which they are attached; and Rc, Rd, Re, Rf, Rg, and Rh are each hydrogen.
In some embodiments, the disclosure relates to a compound of formula (I), (I-A), (I-B), (I-C), (I-D), (I-E), or (I-M), or a pharmaceutically acceptable salt thereof, wherein Ra and Re form a C1-C2 alkylene group between the atoms to which they are attached, wherein said C1-C2 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl. In some embodiments, Ra and Re form a C1-C2 alkylene group between the atoms to which they are attached; and Rb, Rc, Rd, Re, Rf, and Rh are each hydrogen. In some embodiments, Ra and Rb form a C1 alkylene group between the atoms to which they are attached; and Rb, Rc, Rd, Rf, Rg, and Rh are each hydrogen. In some embodiments, Ra and Re form a C2 alkylene group between the atoms to which they are attached; and Rb, Rc, Rd, Rf, Rg, and Rh are each hydrogen.
In some embodiments, the disclosure relates to a compound of formula (I), (I-A), (I-B), (I-C), (I-D), (I-E), or (I-M), or a pharmaceutically acceptable salt thereof, wherein Ra and Rg form a C1-C3 alkylene group between the atoms to which they are attached, wherein said C1-C3 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl. In some embodiments, Ra and Rg form a C1-C3 alkylene group between the atoms to which they are attached; and Rb, Rc, Rd, Re, Rf, and Rh are each hydrogen. In some embodiments, Ra and Rg form a C1 alkylene group between the atoms to which they are attached; and Rb, Rc, Rd, Re, Rf, and Rh are each hydrogen. In some embodiments, Ra and Rg form a C2 alkylene group between the atoms to which they are attached; and Rb, Rc, Rd, Re, Rf, and Rh are each hydrogen. In some embodiments, Ra and Rg form a C3 alkylene group between the atoms to which they are attached; and Rb, Rc, Rd, Re, Rf, and Rh are each hydrogen.
In some embodiments, the disclosure relates to a compound of formula (I), (I-A), (I-B), (I-C), (I-D), (I-E), or (I-M), or a pharmaceutically acceptable salt thereof, wherein Rb and Rc form a C1-C4 alkylene group between the atoms to which they are attached, wherein said C1-C4 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl. In some embodiments, Rb and Rc form a C1-C4 alkylene group between the atoms to which they are attached; and Ra, Rd, Re, Rf, Rg, and Rh are each hydrogen. In some embodiments, Rb and Rc form a C1-C3 alkylene group between the atoms to which they are attached; and Ra, Rd, Rc, Rf, Rg, and Rh are each hydrogen. In some embodiments, Rb and Rc form a C1 alkylene group between the atoms to which they are attached; and Ra, Rd, Re, Rf, Rg, and Rh are each hydrogen. In some embodiments, Rb and Rc form a C2 alkylene group between the atoms to which they are attached; and Ra, Rd, Re, Rf, Rg, and Rh are each hydrogen. In some embodiments, Rb and Rc form a C3 alkylene group between the atoms to which they are attached; and Ra, Rd, Re, Rf, Rg, and Rh are each hydrogen. In some embodiments, Rb and Rc form a C4 alkylene group between the atoms to which they are attached; and Ra, Rd, Re, Rf, Rg, and Rh are each hydrogen.
In some embodiments, the disclosure relates to a compound of formula (I), (I-A), (I-B), (I-C), (I-D), (I-E), or (I-M), or a pharmaceutically acceptable salt thereof, wherein Rb and Re form a C1-C3 alkylene group between the atoms to which they are attached, wherein said C1-C3 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl. In some embodiments, Rb and Re form a C1-C3 alkylene group between the atoms to which they are attached; and Ra, Rc, Rd, Rf, Rg, and Rh are each hydrogen. In some embodiments, Rb and Re form a C1 alkylene group between the atoms to which they are attached; and Ra, Rc, Rd, Rf, Rg, and Rh are each hydrogen. In some embodiments, Rb and Rc form a C2 alkylene group between the atoms to which they are attached; and Ra, Rc, Rd, Rf, Rg, and Rh are each hydrogen. In some embodiments, Rb and Re form a C3 alkylene group between the atoms to which they are attached; and Ra, Rc, Rd, Rf, Rg, and Rh are each hydrogen.
In some embodiments, the disclosure relates to a compound of formula (I), (I-A), (I-B), (I-C), (I-D), (I-E), or (I-M), or a pharmaceutically acceptable salt thereof, wherein Rb and Rg form a C1-C4 alkylene group between the atoms to which they are attached, wherein said C1-C4 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl. In some embodiments, Rb and Rg form a C1-C4 alkylene group between the atoms to which they are attached; and Ra, Rc, Rd, Re, Rf, and Rh are each hydrogen. In some embodiments, Rb and Rg form a C1 alkylene group between the atoms to which they are attached; and Ra, Rc, Rd, Re, Rf, and Rh are each hydrogen. In some embodiments, Rb and Rg form a C2 alkylene group between the atoms to which they are attached; and Ra, Rc, Rd, Re, Rf, and Rh are each hydrogen. In some embodiments, Rb and Rg form a C3 alkylene group between the atoms to which they are attached; and Ra, Rc, Rd, Re, Rf, and Rh are each hydrogen. In some embodiments, Rb and Rg form a C4 alkylene group between the atoms to which they are attached; and Ra, Rc, Rd, Re, Rf, and Rh are each hydrogen.
In some embodiments, the disclosure relates to a compound of formula (I), (I-A), (I-B), (I-C), (I-D), (I-E), or (I-M), or a pharmaceutically acceptable salt thereof, wherein Rc and Rd together with the atom to which they are attached, form a 3-6 membered cycloalkyl or heterocycloalkyl, wherein said 3-6 membered cycloalkyl or heterocycloalkyl is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl. In some embodiments, Rc and Rd together with the atom to which they are attached, form a 3-6 membered cycloalkyl or heterocycloalkyl; and Ra, Rb, Re, Rf, Rg, and Rh are each hydrogen. In some embodiments, Rc and Rd together with the atom to which they are attached, form a 3 membered cycloalkyl or a 4 membered heterocycloalkyl; and Ra, Rb, Re, Rf, Rg, and Rh are each hydrogen. In some embodiments, Rc and Rd together with the atom to which they are attached, form a 3-6 membered cycloalkyl; and Ra, Rb, Re, Rf, Rg, and Rh are each hydrogen. In some embodiments, Rc and Rd together with the atom to which they are attached, form a 3 membered cycloalkyl; and Ra, Rb, Re, Rf, Rg, and Rh are each hydrogen. In some embodiments, Rc and Rd together with the atom to which they are attached, form a 4 membered cycloalkyl; and Ra, Rb, Re, Rf, Rg, and Rh are each hydrogen. In some embodiments, Rc and Rd together with the atom to which they are attached, form a 5 membered cycloalkyl; and Ra, Rb, Re, Rf, Rg, and Rh are each hydrogen. In some embodiments, Rc and Rd together with the atom to which they are attached, form a 6 membered cycloalkyl; and Ra, Rb, Rc, Rf, Rg, and Rh are each hydrogen. In some embodiments, Rc and Rd together with the atom to which they are attached, form a 3-6 membered heterocycloalkyl ring; and Ra, Rb, Re, Rf, Rg, and Rh are each hydrogen. In some embodiments, Rc and Rd together with the atom to which they are attached, form a 3-6 membered heterocycloalkyl ring, wherein the 3-6 membered heterocycloalkyl ring contains 0, S, or NH; and Ra, Rb, Re, Rf, Rg, and Rh are each hydrogen. In some embodiments, Rc and Rd together with the atom to which they are attached, form a 3 membered heterocycloalkyl ring; and Ra, Rb, Re, Rf, Rb, and Rh are each hydrogen. In some embodiments, Rc and Rd together with the atom to which they are attached, form a 4 membered heterocycloalkyl ring; and Ra, Rb, Re, Rf, Rg, and Rh are each hydrogen. In some embodiments, Rc and Rd together with the atom to which they are attached, form an oxetane ring; and Ra, Rb, Re, Rf, Rg, and Rh are each hydrogen. In some embodiments, Rc and Rd together with the atom to which they are attached, form a 5 membered heterocycloalkyl ring; and Ra, Rb, Re, Rf, Rg, and Rh are each hydrogen. In some embodiments, Rc and Rd together with the atom to which they are attached, form a 6 membered heterocycloalkyl ring; and Ra, Rb, Re, Rf, Rg, and Rh are each hydrogen. In some embodiments, Re and Rd together form ═O. In some embodiments, Rc and Rd together form ═O; and Ra, Rb, Re, Rf, Rg, and Rh are each hydrogen.
In some embodiments, the disclosure relates to a compound of formula (I), (I-A), (I-B), (I-C), (I-D), (I-E), or (I-M), or a pharmaceutically acceptable salt thereof, wherein Rc and Re form a C1-C4 alkylene group between the atoms to which they are attached, wherein said C1-C4 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl. In some embodiments, Rc and Re form a C1-C4 alkylene group between the atoms to which they are attached; and Ra, Rb, Rd, Rf, Rg, and Rh are each hydrogen. In some embodiments, Rc and Re form a C1 alkylene group between the atoms to which they are attached; and Ra, Rb, Rd, Rf, Rg, and Rh are each hydrogen. In some embodiments, Rc and Re form a C2 alkylene group between the atoms to which they are attached; and Ra, Rb, Rd, Rf, Rg, and Rh are each hydrogen. In some embodiments, Rc and Re form a C3 alkylene group between the atoms to which they are attached; and Ra, Rb, Rd, Rf, Rg, and Rh are each hydrogen. In some embodiments, Rc and Re form a C4 alkylene group between the atoms to which they are attached; and Ra, Rb, Rd, Rf, Rg, and Rh are each hydrogen.
In some embodiments, the disclosure relates to a compound of formula (I), (I-A), (I-B), (I-C), (I-D), (I-E), or (I-M), or a pharmaceutically acceptable salt thereof, wherein Rc and Rg form a C1-C3 alkylene group between the atoms to which they are attached, wherein said C1-C3 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl. In some embodiments, Rc and Rg form a C1-C3 alkylene group between the atoms to which they are attached; and Ra, Rb, Rd, Re, Rf, and Rh are each hydrogen. In some embodiments, Rc and Rg form a C1-C2 alkylene group between the atoms to which they are attached; and Ra, Rb, Rd, Re, Rf, and Rh are each hydrogen. In some embodiments, Rc and Rg form a C1 alkylene group between the atoms to which they are attached; and Ra, Rb, Rd, Re, Rf, and Rh are each hydrogen. In some embodiments, Rc and Rg form a C2 alkylene group between the atoms to which they are attached; and Ra, Rb, Rd, Re, Rf, and Rh are each hydrogen. In some embodiments, Rc and Rg form a C3 alkylene group between the atoms to which they are attached; and Ra, Rb, Rd, Re, Rf, and Rh are each hydrogen.
In some embodiments, the disclosure relates to a compound of formula (I), (I-A), (I-B), (I-C), (I-D), (I-E), or (I-M), or a pharmaceutically acceptable salt thereof, wherein Re and Rf together with the atom to which they are attached, form a 3-6 membered cycloalkyl or heterocycloalkyl, wherein said 3-6 membered cycloalkyl or heterocycloalkyl is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl. In some embodiments, Re and Rf together with the atom to which they are attached, form a 3-6 membered cycloalkyl or heterocycloalkyl; and Ra, Rb, Rc, Rd, Rg, and Rh are each hydrogen. In some embodiments, Re and Rf together with the atom to which they are attached, form a 3-6 membered cycloalkyl; and Ra, Rb, Rc, Rd, Rg, and Rh are each hydrogen. In some embodiments, Re and Rf together with the atom to which they are attached, form a 3 membered cycloalkyl; and Ra, Rb, Rc, Rd, Rg, and Rh are each hydrogen. In some embodiments, Re and Rf together with the atom to which they are attached, form a 4 membered cycloalkyl; and Ra, Rb, Rc, Rd, Rg, and Rh are each hydrogen. In some embodiments, Re and Rf together with the atom to which they are attached, form a 5 membered cycloalkyl; and Ra, Rb, Rc, Rd, Rg, and Rh are each hydrogen. In some embodiments, Re and Rf together with the atom to which they are attached, form a 6 membered cycloalkyl; and Ra, Rb, Rc, Rd, Rg, and Rh are each hydrogen. In some embodiments, Re and Rf together with the atom to which they are attached, form a 3-6 membered heterocycloalkyl ring; and Ra, Rb, Rc, Rd, Rg, and Rh are each hydrogen. In some embodiments, Re and Rf together with the atom to which they are attached, form a 3-6 membered heterocycloalkyl ring, wherein the 3-6 membered heterocycloalkyl ring contains 0, S, or NH; and Ra, Rb, Rc, Rd, Rg, and Rh are each hydrogen. In some embodiments, Re and Rf together with the atom to which they are attached, form a 3 membered heterocycloalkyl ring; and Ra, Rb, Re, Rd, Rg, and Rh are each hydrogen. In some embodiments, Re and Rf together with the atom to which they are attached, form a 4 membered heterocycloalkyl ring; and Ra, Rb, Rc, Rd, Rg, and Rh are each hydrogen. In some embodiments, Re and Rf together with the atom to which they are attached, form an oxetane ring; and Ra, Rb, Rc, Rd, Rg, and Rh are each hydrogen. In some embodiments, Re and Rf together with the atom to which they are attached, form a 5 membered heterocycloalkyl ring; and Ra, Rb, Rc, Rd, Rg, and Rh are each hydrogen. In some embodiments, Re and Rf together with the atom to which they are attached, form a 6 membered heterocycloalkyl ring; and Ra, Rb, Rc, Rd, Rg, and Rh are each hydrogen. In some embodiments, Re and Rf together form ═O. In some embodiments, Re and Rf together form ═O; and Ra, Rb, Re, Rd, Rg, and Rh are each hydrogen.
In some embodiments, the disclosure relates to a compound of formula (I), (I-A), (I-B), (I-C), (I-D), (I-E), or (I-M), or a pharmaceutically acceptable salt thereof, wherein Re and Rg form a C1-C3 alkylene group between the atoms to which they are attached, wherein said C1-C3 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl. In some embodiments, Re and Rg form a C1-C3 alkylene group between the atoms to which they are attached; and Ra, Rb, Rc, Rd, Rf, and Rh are each hydrogen. In some embodiments, Re and Rg form a C1 alkylene group between the atoms to which they are attached; and Ra, Rb, Rc, Rd, Rf, and Rh are each hydrogen. In some embodiments, Re and Rg form a C2 alkylene group between the atoms to which they are attached; and Ra, Rb, Rc, Rd, Rf, and Rh are each hydrogen. In some embodiments, Re and Rg form a C3 alkylene group between the atoms to which they are attached; and Ra, Rb, Rc, Rd, Rf, and Rh are each hydrogen.
In some embodiments, the disclosure relates to a compound of formula (I), (I-A), (I-B), (I-C), (I-D), (I-E), or (I-M), or a pharmaceutically acceptable salt thereof, wherein Rg and Rh together with the atom to which they are attached, form a 3-6 membered cycloalkyl or heterocycloalkyl, wherein said 3-6 membered cycloalkyl or heterocycloalkyl is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl. In some embodiments, Rg and Rh together with the atom to which they are attached, form a 3-6 membered cycloalkyl or heterocycloalkyl; and Ra, Rb, Rc, Rd, Re, and Rf are each hydrogen. In some embodiments, Rg and Rh together with the atom to which they are attached, form a 3-6 membered cycloalkyl; and Ra, Rb, Rc, Rd, Re, and Rf are each hydrogen. In some embodiments, Rg and Rh together with the atom to which they are attached, form a 3 membered cycloalkyl; and Ra, Rb, Rc, Rd, Re, and Rf are each hydrogen. In some embodiments, Rg and Rh together with the atom to which they are attached, form a 4 membered cycloalkyl; and Ra, Rb, Rc, Rd, Re, and Rf are each hydrogen. In some embodiments, Rg and Rh together with the atom to which they are attached, form a 5 membered cycloalkyl; and Ra, Rb, Rc, Rd, Re, and Rf are each hydrogen. In some embodiments, Rg and Rh together with the atom to which they are attached, form a 6 membered cycloalkyl; and Ra, Rb, Rc, Rd, Re, and Rf are each hydrogen. In some embodiments, Rg and Rh together with the atom to which they are attached, form a 3-6 membered heterocycloalkyl ring; and Ra, Rb, Rc, Rd, Re, and Rf are each hydrogen. In some embodiments, Rg and Rh together with the atom to which they are attached, form a 3-6 membered heterocycloalkyl ring, wherein the 3-6 membered heterocycloalkyl ring contains 0, S, or NH; and Ra, Rb, Rc, Rd, Re, and Rf are each hydrogen. In some embodiments, Rg and Rh together with the atom to which they are attached, form a 3 membered heterocycloalkyl ring; and Ra, Rb, Rc, Rd, Re, and Rf are each hydrogen. In some embodiments, Rg and Rh together with the atom to which they are attached, form a 4 membered heterocycloalkyl ring; and Ra, Rb, Rc, Rd, Re, and Rf are each hydrogen. In some embodiments, Rg and Rh together with the atom to which they are attached, form an oxetane ring; and Ra, Rb, Rc, Rd, Rc, and Rf are each hydrogen. In some embodiments, Rg and Rh together with the atom to which they are attached, form a 5 membered heterocycloalkyl ring; and Ra, Rb, Rc, Rd, Re, and Rf are each hydrogen. In some embodiments, Rg and Rh together with the atom to which they are attached, form a 6 membered heterocycloalkyl ring; and Ra, Rb, Rc, Rd, Re, and Rf are each hydrogen. In some embodiments, Rg and Rh together form ═O. In some embodiments, Rg and Rh together form ═O; and Ra, Rb, Re, Rd, Re, and Rf are each hydrogen.
In some embodiments, the disclosure relates to a compound of formula (I), (I-A), (I-B), (I-C), (I-D), (I-E), or (I-M), or a pharmaceutically acceptable salt thereof, wherein Ra, Rb, Rc, Rd, Re, Rf, Rg, and Rh are defined as follows:
    • (ii) Ra and Re form a C1-C2 alkylene group between the atoms to which they are attached, wherein said C1-C2 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Rb, Rc, Rd, Rf, Rg, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
    • (iv) Rb and Re form a C1-C4 alkylene group between the atoms to which they are attached, wherein said C1-C4 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Ra, Rd, Re, Rf, Rg, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
    • (vii) Re and Rd together with the atom to which they are attached, form a 3-6 membered cycloalkyl or heterocycloalkyl, wherein said 3-6 membered cycloalkyl or heterocycloalkyl is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Ra, Rb, Re, Rf, Rg, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
    • (viii) Re and Rd together form ═O; and Ra, Rb, Re, Rf, Rg, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
    • (ix) Re and Rc form a C1-C4 alkylene group between the atoms to which they are attached, wherein said C1-C4 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Ra, Rb, Rd, Rf, Rg, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
    • (x) Rc and Rg form a C1-C3 alkylene group between the atoms to which they are attached, wherein said C1-C3 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Ra, Rb, Rd, Re, Rf, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
    • (xi) Re and Rf together with the atom to which they are attached, form a 3-6 membered cycloalkyl or heterocycloalkyl, wherein said 3-6 membered cycloalkyl or heterocycloalkyl is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Ra, Rb, Rc, Rd, Rg, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
    • (xiii) Re and Rg form a C1-C3 alkylene group between the atoms to which they are attached, wherein said C1-C3 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Ra, Rb, Rc, Rd, Rf, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
    • (xv) Rg and Rh together form ═O; and Ra, Rb, Rc, Rd, Re, and BW are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl.
In some embodiments, the disclosure relates to a compound of formula (I), (I-A), (I-B), (I-C), (I-D), (I-E), or (I-M), or a pharmaceutically acceptable salt thereof, wherein Ra, Rb, Re, Rd, Re, Rf, Rg, and Rh are defined as follows:
    • (ii) Ra and Re form a C1-C2 alkylene group between the atoms to which they are attached; and Rb, Rc, Rd, Rf, Rg, and Rh are each hydrogen; or
    • (iv) Rb and Rc form a C1-C4 alkylene group between the atoms to which they are attached; and Ra, Rd, Re, Rf, Rg, and Rh are each hydrogen; or
    • (vii) Re and Rd together with the atom to which they are attached, form a 3-6 membered cycloalkyl or heterocycloalkyl; and Ra, Rb, Re, Rf, Rg, and Rh are each hydrogen; or
    • (viii) Re and Rd together form ═O; and Ra, Rb, Re, Rf, Rg, and Rh are each hydrogen; or
    • (ix) Re and Rc form a C1-C4 alkylene group between the atoms to which they are attached; and Ra, Rb, Rd, Rf, Rg, and Rh are each hydrogen; or
    • (x) Re and RY form a C1-C3 alkylene group between the atoms to which they are attached; and Ra, Rb, Rd, Re, Rf, and Rh are each hydrogen; or
    • (xi) Re and Rf together with the atom to which they are attached, form a 3-6 membered cycloalkyl or heterocycloalkyl; and Ra, Rb, Rc, Rd, Rg, and Rh are each hydrogen; or
    • (xiii) Re and Rg form a C1-C3 alkylene group between the atoms to which they are attached; and Ra, Rb, Rc, Rd, BW, and Rh are each independently hydrogen; or
    • (xv) Rg and Rh together form ═O; and Ra, Rb, Rc, Rd, Re, and Rf are each hydrogen.
In some embodiments, the disclosure relates to a compound of formula (I), (I-A), (I-B), (I-C), (I-D), (I-E), or (I-M), or a pharmaceutically acceptable salt thereof, wherein Ra, Rb, Re, Rd, Re, Rf, Rg, and Rh are defined as follows:
    • (ii) Ra and Re form a C1-C2 alkylene group between the atoms to which they are attached; and Rb, Rc, Rd, Rf, Rg, and Rh are each hydrogen; or
    • (iv) Rb and Rc form a C1-C3 alkylene group between the atoms to which they are attached; and Ra, Rd, Re, Rf, Rg, and Rh are each hydrogen; or
    • (vii) Re and Rd together with the atom to which they are attached, form a 3-membered cycloalkyl or a 4-membered heterocycloalkyl; and Ra, Rb, Re, Rf, Rg, and Rh are each hydrogen; or
    • (viii) Re and Rd together form ═O; and Ra, Rb, Re, Rf, Rg, and Rh are each hydrogen; or
    • (ix) Rc and Re form a C1 alkylene group between the atoms to which they are attached; and Ra, Rb, Rd, Rf, Rg, and Rh are each hydrogen; or
    • (x) Rc and Rg form a C1-C2 alkylene group between the atoms to which they are attached; and Ra, Rb, Rd, Re, Rf, and Rh are each hydrogen; or
    • (xi) Re and Rf together with the atom to which they are attached, form a 4-membered heterocycloalkyl; and Ra, Rb, Rc, Rd, Rg, and Rh are each hydrogen; or
    • (xiii) Re and Rg form a C2 alkylene group between the atoms to which they are attached; and Ra, Rb, Rc, Rd, Rf, and Rh are each independently hydrogen; or
    • (xv) Rg and Rh together form ═O; and Ra, Rb, Rc, Rd, Re, and Rf are each hydrogen.
In some embodiments, the disclosure relates to a compound of formula (I), (I-A), (I-B), (I-C), (I-D), (I-E), or (I-M), or a pharmaceutically acceptable salt thereof, wherein Ra, Rb, Rc, Rd, Re, Rf, Rg, and Rh are defined as follows:
    • (ii) Ra and Re form a C1-C2 alkylene group between the atoms to which they are attached; and Rb, Rc, Rd, Rf, and R9 are each hydrogen; or
    • (iv) Rb and Re form a C1-C2 alkylene group between the atoms to which they are attached; and Ra, Rb, Rd, Rf, and Rg are each hydrogen; or
    • (vii) Re and Rd together with the atom to which they are attached, form a 3 membered cycloalkyl; and Ra, Rb, Re, Rf, and Rg are each hydrogen; or
    • (x) Re and Rh form a C1-C2 alkylene group between the atoms to which they are attached; and Ra, Rb, Rd, Re, and Rf are each hydrogen; or
    • (xi) Re and Rf together with the atom to which they are attached, form a 4 membered heterocycloalkyl; and Ra, Rb, Rc, Rd, and R9 are each hydrogen; or
    • (xiii) Re and Rg form a C2 alkylene group between the atoms to which they are attached;
    • and Ra, Rb, Rc, Rd, and Rf are each independently hydrogen.
In some embodiments, the disclosure relates to a compound of formula (I), (I-A), (I-B), (I-C), (I-D), (I-E), or (I-M), or a pharmaceutically acceptable salt thereof, wherein
Figure US11814386-20231114-C00056
is selected from:
Figure US11814386-20231114-C00057
In some embodiments,
Figure US11814386-20231114-C00058
In some embodiments,
Figure US11814386-20231114-C00059
In some embodiments,
Figure US11814386-20231114-C00060
In some embodiments,
Figure US11814386-20231114-C00061
In some embodiments,
Figure US11814386-20231114-C00062
In some embodiments,
Figure US11814386-20231114-C00063
In some embodiments,
Figure US11814386-20231114-C00064
In some embodiments,
Figure US11814386-20231114-C00065
In some embodiments,
Figure US11814386-20231114-C00066
In some embodiments,
Figure US11814386-20231114-C00067
In some embodiments,
Figure US11814386-20231114-C00068
In some embodiments, the disclosure relates to a compound of formula (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-B), (I-B-1), (I-B-2), (I-B-3), (I-B-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), (I-L-2), (I-M), (I-M-1), (I-M-2), (I-M-3), or (I-M-4), or a pharmaceutically acceptable salt thereof, wherein X1 is C or N. In some embodiments, X1 is C. In some embodiments, X1 is N.
In some embodiments, the disclosure relates to a compound of formula (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-B), (I-B-1), (I-B-2), (I-B-3), (I-B-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), (I-L-2), (I-M), (I-M-1), (I-M-2), (I-M-3), or (I-M-4), or a pharmaceutically acceptable salt thereof, wherein X2 is CH, CR1, O, S, N, NH, or NR1, as valency permits. In some embodiments, X2 is CH. In some embodiments, X2 is CR1. In some embodiments, X2 is O. In some embodiments, X2 is S. In some embodiments, X2 is N. In some embodiments, X2 is NH. In some embodiments, X2 is NR1.
In some embodiments, the disclosure relates to a compound of formula (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-B), (I-B-1), (I-B-2), (I-B-3), (I-B-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), (I-L-2), (I-M), (I-M-1), (I-M-2), (I-M-3), or (I-M-4), or a pharmaceutically acceptable salt thereof, wherein X3 is CH, CR1, O, S, N, NH, or NR1, as valency permits. In some embodiments, X3 is CH. In some embodiments, X3 is CR1. In some embodiments, X3 is O. In some embodiments, X3 is S. In some embodiments, X3 is N. In some embodiments, X3 is NH. In some embodiments, X3 is NR1.
In some embodiments, the disclosure relates to a compound of formula (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-B), (I-B-1), (I-B-2), (I-B-3), (I-B-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), (I-L-2), (I-M), (I-M-1), (I-M-2), (I-M-3), or (I-M-4), or a pharmaceutically acceptable salt thereof, wherein X4 is C or N. In some embodiments, X4 is C. In some embodiments, X4 is N.
In some embodiments, the disclosure relates to a compound of formula (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), (I-L-2), (I-M), (I-M-1), (I-M-2), (I-M-3), or (I-M-4), or a pharmaceutically acceptable salt thereof, wherein X5 is a bond, CH, CR1, O, S, N, NH, or NR1, as valency permits. In some embodiments, X5 is a bond. In some embodiments, X5 is CH. In some embodiments, X5 is CR1. In some embodiments, X5 is O. In some embodiments, X5 is S. In some embodiments, X5 is N. In some embodiments, X5 is NH. In some embodiments, X5 is NR1.
In some embodiments, the disclosure relates to a compound of formula (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-B), (I-B-1), (I-B-2), (I-B-3), (I-B-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), (I-L-2), (I-M), (I-M-1), (I-M-2), (I-M-3), or (I-M-4), or a pharmaceutically acceptable salt thereof, wherein X6 is CH, CR1, O, S, N, NH, or NR1, as valency permits. In some embodiments, X6 is CH. In some embodiments, X6 is CR1. In some embodiments, X6 is O. In some embodiments, X6 is S. In some embodiments, X6 is N. In some embodiments, X6 is NH. In some embodiments, X6 is NR1.
In some embodiments, the disclosure relates to a compound of formula (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), (I-L-2), (I-M), (I-M-1), (I-M-2), (I-M-3), or (I-M-4), or a pharmaceutically acceptable salt thereof, wherein X1 is C; X2 is N; X3 is NH; X4 is C; X5 is a bond; and X6 is CH.
In some embodiments, the disclosure relates to a compound of formula (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), (I-L-2), (I-M), (I-M-1), (I-M-2), (I-M-3), or (I-M-4), or a pharmaceutically acceptable salt thereof, wherein X1 is C; X2 is N; X3 is CH; X4 is C; X5 is a bond; and X6 is S.
In some embodiments, the disclosure relates to a compound of formula (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), (I-L-2), (I-M), (I-M-1), (I-M-2), (I-M-3), or (I-M-4), or a pharmaceutically acceptable salt thereof, wherein X1 is C; X2 is CH; X3 is CH; X4 is C; X5 is CH; and X6 is C.
In some embodiments, the disclosure relates to a compound of formula (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-F7-1), (I-F7-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), or (I-L-2), or a pharmaceutically acceptable salt thereof, wherein Y1 is C or N. In some embodiments, Y1 is C. In some embodiments, Y1 is N.
In some embodiments, the disclosure relates to a compound of formula (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), or (I-L-2), or a pharmaceutically acceptable salt thereof, wherein Y2 is C or N. In some embodiments, Y2 is C. In some embodiments, Y2 is N.
In some embodiments, the disclosure relates to a compound of formula (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-B), (I-B-1), (I-B-2), (I-B-3), (I-B-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), or (I-L-2), or a pharmaceutically acceptable salt thereof, wherein Y3 is CH, CR2, O, S, N, NH, or NR2, as valency permits. In some embodiments, Y3 is CH. In some embodiments, Y3 is CR2. In some embodiments, Y3 is 0. In some embodiments, Y3 is S. In some embodiments, Y3 is N. In some embodiments, Y3 is NH. In some embodiments, Y3 is NR2.
In some embodiments, the disclosure relates to a compound of formula (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-B), (I-B-1), (I-B-2), (I-B-3), (I-B-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), or (I-L-2), or a pharmaceutically acceptable salt thereof, wherein Y4 is a bond, CH, CR2, O, S, N, NH, or NR2, as valency permits. In some embodiments, Y4 is a bond. In some embodiments, Y4 is CH. In some embodiments, Y4 is CR2. In some embodiments, Y4 is O. In some embodiments, Y4 is S. In some embodiments, Y4 is N. In some embodiments, Y4 is NH. In some embodiments, Y4 is NR2.
In some embodiments, the disclosure relates to a compound of formula (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-B), (I-B-1), (I-B-2), (I-B-3), (I-B-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), or (I-L-2), or a pharmaceutically acceptable salt thereof, wherein Y5 is CH, CR2, O, S, N, NH, or NR2, as valency permits. In some embodiments, Y5 is CH. In some embodiments, Y5 is CR2. In some embodiments, Y5 is O. In some embodiments, Y5 is S. In some embodiments, Y5 is N. In some embodiments, Y5 is NH. In some embodiments, Y5 is NR2.
In some embodiments, the disclosure relates to a compound of formula (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-B), (I-B-1), (I-B-2), (I-B-3), (I-B-4), (I-F7-1), (I-F7-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), or (I-L-2), or a pharmaceutically acceptable salt thereof, wherein Y6 is CH, CR2, O, S, N, NH, or NR2, as valency permits. In some embodiments, Y6 is CH. In some embodiments, Y6 is CR2. In some embodiments, Y6 is 0. In some embodiments, Y6 is S. In some embodiments, Y6 is N. In some embodiments, Y6 is NH. In some embodiments, Y6 is NR2.
In some embodiments, the disclosure relates to a compound of formula (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), or (I-L-2), or a pharmaceutically acceptable salt thereof, wherein Y1 is C; Y2 is C; Y3 is CH; Y4 is CH; Y5 is CH; and Y6 is CH.
In some embodiments, the disclosure relates to a compound of formula (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), or (I-L-2), or a pharmaceutically acceptable salt thereof, wherein Y1 is C; Y2 is C; Y3 is CR2; Y4 is CH; Y5 is CH; and Y6 is CH.
In some embodiments, the disclosure relates to a compound of formula (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-F7-1), (I-F7-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), or (I-L-2), or a pharmaceutically acceptable salt thereof, wherein Y1 is C; Y2 is C; Y3 is CH; Y4 is CR2; Y5 is CH; and Y6 is CH.
In some embodiments, the disclosure relates to a compound of formula (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), or (I-L-2), or a pharmaceutically acceptable salt thereof, wherein Y1 is C; Y2 is C; Y3 is CH; Y4 is CH; Y5 is CR2; and Y6 is CH.
In some embodiments, the disclosure relates to a compound of formula (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), or (I-L-2), or a pharmaceutically acceptable salt thereof, wherein Y1 is C; Y2 is C; Y3 is N; Y4 is CH; Y5 is CH; and Y6 is CR2. In some embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein Y1 is C; Y2 is C; Y3 is N; Y4 is CH; Y5 is CH; and Y6 is CH.
In some embodiments, the disclosure relates to a compound of formula (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), or (I-L-2), or a pharmaceutically acceptable salt thereof, wherein Y1 is C; Y2 is C; Y3 is CH; Y4 is N; Y5 is CH; and Y6 is CH.
In some embodiments, the disclosure relates to a compound of formula (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), or (I-L-2), or a pharmaceutically acceptable salt thereof, wherein Y1 is C; Y2 is C; Y3 is CH; Y4 is CH; Y is N; and Y6 is CH.
In some embodiments, the disclosure relates to a compound of formula (I-A), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-F-1), (I-F-2), (I-G-1), (I-G-2), (I-H-1), (I-H-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), or (I-L-2), or a pharmaceutically acceptable salt thereof, wherein Y1 is C; Y2 is C; Y3 is CH; Y4 is CH; Y5 is CH; and Y6 is N.
In some embodiments, the disclosure relates to a compound of formula (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-B-1), (I-B-2), (I-B-3), (I-B-4), (I-C-1), (I-C-2), (I-C-3), (I-C-4), (I-M-1), (I-M-2), (I-M-3), or (I-M-4), or a pharmaceutically acceptable salt thereof, wherein Rj, Rk, Rm, Rn, Ro, Rp, Rq, and Rr, when present, are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl. In some embodiments, Rj, Rk, Rm, Rn, Ro, Rp, Rq, and Rr, when present, are each hydrogen.
In some embodiments, the disclosure relates to a compound of formula (I-B), (I-B-1), (I-B-2), (I-B-3), or (I-B-4), or a pharmaceutically acceptable salt thereof, wherein X1 is C; X2 is N; X3 is NH; X4 is C; and X6 is CH.
In some embodiments, the disclosure relates to a compound of formula (I-B), (I-B-1), (I-B-2), (I-B-3), or (I-B-4), or a pharmaceutically acceptable salt thereof, wherein X1 is C; X2 is N; X3 is CH; X4 is C; and X6 is S.
In some embodiments, the disclosure relates to a compound of formula (I-B), (I-B-1), (I-B-2), (I-B-3), or (I-B-4), or a pharmaceutically acceptable salt thereof, wherein Y3 is CH; Y4 is CH; Y5 is CH; and Y6 is CH.
In some embodiments, the disclosure relates to a compound of formula (I-B), (I-B-1), (I-B-2), (I-B-3), or (I-B-4), or a pharmaceutically acceptable salt thereof, wherein Y3 is CR2; Y4 is CH; Y5 is CH; and Y6 is CH.
In some embodiments, the disclosure relates to a compound of formula (I-B), (I-B-1), (I-B-2), (I-B-3), or (I-B-4), or a pharmaceutically acceptable salt thereof, wherein Y3 is CH; Y4 is CR2; Y5 is CH; and Y6 is CH.
In some embodiments, the disclosure relates to a compound of formula (I-B), (I-B-1), (I-B-2), (I-B-3), or (I-B-4), or a pharmaceutically acceptable salt thereof, wherein Y3 is CH; Y4 is CH; Y5 is CR2; and Y6 is CH.
In some embodiments, the disclosure relates to a compound of formula (I-B), (I-B-1), (I-B-2), (I-B-3), or (I-B-4), or a pharmaceutically acceptable salt thereof, wherein Y3 is CH; Y4 is CH; Y5 is CH; and Y6 is CR2.
In some embodiments, the disclosure relates to a compound of formula (I-B), (I-B-1), (I-B-2), (I-B-3), or (I-B-4), or a pharmaceutically acceptable salt thereof, wherein Y3 is N; Y4 is CH; Y5 is CH; and Y6 is CH.
In some embodiments, the disclosure relates to a compound of formula (I-B), (I-B-1), (I-B-2), (I-B-3), or (I-B-4), or a pharmaceutically acceptable salt thereof, wherein Y3 is CH; Y4 is N; Y5 is CH; and Y6 is CH.
In some embodiments, the disclosure relates to a compound of formula (I-B), (I-B-1), (I-B-2), (I-B-3), or (I-B-4), or a pharmaceutically acceptable salt thereof, wherein Y3 is CH; Y4 is CH; Y5 is N; and Y6 is CH.
In some embodiments, the disclosure relates to a compound of formula (I-B), (I-B-1), (I-B-2), (I-B-3), or (I-B-4), or a pharmaceutically acceptable salt thereof, wherein Y3 is CH; Y4 is CH; Y5 is CH; and Y6 is N.
In some embodiments, the disclosure relates to a compound provided herein, or a pharmaceutically acceptable salt thereof, that is a USP30 Inhibitor Compound having an IC50 value of ≤1 μM and >0.001 μM as measured in a Ubiquitin-Rhodamine 110 Assay as described in Example 1.
In another aspect, the disclosure relates to a compound selected from Table 1, or a pharmaceutically acceptable salt thereof. Each pair of compounds listed in Table 1 (i.e., compounds 1-a and 1-b, compounds 2-a and 2-b, etc.) was obtained as a racemic mixture, and were then separated by chiral HPLC according to the procedure described in Example 2, Step 7, or a similar method, to obtain the individual compounds in substantially enantiomerically pure form. For each pair of compounds, the first compound (i.e., compounds 1-a, 2-a, etc.) was the first eluting isomer, and the second compound (i.e., compounds 1-b, 2-b, etc.) was the second eluting isomer. The stereochemical descriptors reflect the relative stereochemistry of each compound. The absolute stereochemistry of each compound was arbitrarily assigned. In some embodiments, the compound selected from Table 1, or a pharmaceutically acceptable salt thereof, is present in a racemic mixture. In some embodiments, the compound selected from Table 1, or a pharmaceutically acceptable salt thereof, is present in substantially enantiomerically pure form.
TABLE 1
Compounds of the Disclosure
Compound
Number Compound Structure and Chemical Name
 1-a
Figure US11814386-20231114-C00069
 1-b
Figure US11814386-20231114-C00070
 2-a
Figure US11814386-20231114-C00071
 2-b
Figure US11814386-20231114-C00072
 3-a
Figure US11814386-20231114-C00073
 3-b
Figure US11814386-20231114-C00074
 4-a
Figure US11814386-20231114-C00075
 4-b
Figure US11814386-20231114-C00076
 5-a
Figure US11814386-20231114-C00077
 5-b
Figure US11814386-20231114-C00078
 6-a
Figure US11814386-20231114-C00079
 6-b
Figure US11814386-20231114-C00080
 7-a
Figure US11814386-20231114-C00081
 7-b
Figure US11814386-20231114-C00082
 8-a
Figure US11814386-20231114-C00083
 8-b
Figure US11814386-20231114-C00084
 9-a
Figure US11814386-20231114-C00085
 9-b
Figure US11814386-20231114-C00086
13-a
Figure US11814386-20231114-C00087
13-b
Figure US11814386-20231114-C00088
20-a
Figure US11814386-20231114-C00089
20-b
Figure US11814386-20231114-C00090
In another aspect, the disclosure relates to a compound selected from Table 2, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is present in a racemic mixture with its enantiomer. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is present in substantially enantiomerically pure form.
In another aspect, the disclosure relates to the enantiomer of a compound selected from Table 2, or a pharmaceutically acceptable salt thereof. In some embodiments, the enantiomer, or a pharmaceutically acceptable salt thereof, is present in a racemic mixture. In some embodiments, the enantiomer, or a pharmaceutically acceptable salt thereof, is present in substantially enantiomerically pure form.
TABLE 2
Compounds of the Disclosure
Compound
Number Compound Structure and Chemical Name
 10
Figure US11814386-20231114-C00091
 11
Figure US11814386-20231114-C00092
 12
Figure US11814386-20231114-C00093
 13
Figure US11814386-20231114-C00094
 14
Figure US11814386-20231114-C00095
 15
Figure US11814386-20231114-C00096
 16
Figure US11814386-20231114-C00097
 17
Figure US11814386-20231114-C00098
 18
Figure US11814386-20231114-C00099
 19
Figure US11814386-20231114-C00100
 20
Figure US11814386-20231114-C00101
 21
Figure US11814386-20231114-C00102
 22
Figure US11814386-20231114-C00103
 23
Figure US11814386-20231114-C00104
 24
Figure US11814386-20231114-C00105
 25
Figure US11814386-20231114-C00106
 26
Figure US11814386-20231114-C00107
 27
Figure US11814386-20231114-C00108
 28
Figure US11814386-20231114-C00109
 29
Figure US11814386-20231114-C00110
 30
Figure US11814386-20231114-C00111
 31
Figure US11814386-20231114-C00112
 32
Figure US11814386-20231114-C00113
 33
Figure US11814386-20231114-C00114
 34
Figure US11814386-20231114-C00115
 35
Figure US11814386-20231114-C00116
 36
Figure US11814386-20231114-C00117
 37
Figure US11814386-20231114-C00118
 38
Figure US11814386-20231114-C00119
 39
Figure US11814386-20231114-C00120
 40
Figure US11814386-20231114-C00121
 41
Figure US11814386-20231114-C00122
 42
Figure US11814386-20231114-C00123
 43
Figure US11814386-20231114-C00124
 44
Figure US11814386-20231114-C00125
 45
Figure US11814386-20231114-C00126
 46
Figure US11814386-20231114-C00127
 47
Figure US11814386-20231114-C00128
 48
Figure US11814386-20231114-C00129
 49
Figure US11814386-20231114-C00130
 50
Figure US11814386-20231114-C00131
 51
Figure US11814386-20231114-C00132
 52
Figure US11814386-20231114-C00133
 53
Figure US11814386-20231114-C00134
 54
Figure US11814386-20231114-C00135
 55
Figure US11814386-20231114-C00136
 56
Figure US11814386-20231114-C00137
 57
Figure US11814386-20231114-C00138
 58
Figure US11814386-20231114-C00139
 59
Figure US11814386-20231114-C00140
 60
Figure US11814386-20231114-C00141
 61
Figure US11814386-20231114-C00142
 62
Figure US11814386-20231114-C00143
 63
Figure US11814386-20231114-C00144
 64
Figure US11814386-20231114-C00145
 65
Figure US11814386-20231114-C00146
 66
Figure US11814386-20231114-C00147
 67
Figure US11814386-20231114-C00148
 68
Figure US11814386-20231114-C00149
 69
Figure US11814386-20231114-C00150
 70
Figure US11814386-20231114-C00151
 71
Figure US11814386-20231114-C00152
 72
Figure US11814386-20231114-C00153
 73
Figure US11814386-20231114-C00154
 74
Figure US11814386-20231114-C00155
 75
Figure US11814386-20231114-C00156
 76
Figure US11814386-20231114-C00157
 77
Figure US11814386-20231114-C00158
 78
Figure US11814386-20231114-C00159
 79
Figure US11814386-20231114-C00160
 80
Figure US11814386-20231114-C00161
 81
Figure US11814386-20231114-C00162
 82
Figure US11814386-20231114-C00163
 83
Figure US11814386-20231114-C00164
 84
Figure US11814386-20231114-C00165
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Figure US11814386-20231114-C00166
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Figure US11814386-20231114-C00167
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Figure US11814386-20231114-C00168
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Figure US11814386-20231114-C00169
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Figure US11814386-20231114-C00170
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Figure US11814386-20231114-C00171
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Figure US11814386-20231114-C00172
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Figure US11814386-20231114-C00173
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Figure US11814386-20231114-C00174
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Figure US11814386-20231114-C00175
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Figure US11814386-20231114-C00176
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Figure US11814386-20231114-C00177
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Figure US11814386-20231114-C00178
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Figure US11814386-20231114-C00179
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Figure US11814386-20231114-C00180
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Figure US11814386-20231114-C00181
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Figure US11814386-20231114-C00182
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Figure US11814386-20231114-C00183
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Figure US11814386-20231114-C00184
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Figure US11814386-20231114-C00185
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Figure US11814386-20231114-C00186
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Figure US11814386-20231114-C00187
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Figure US11814386-20231114-C00188
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Figure US11814386-20231114-C00189
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Figure US11814386-20231114-C00190
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Figure US11814386-20231114-C00191
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Figure US11814386-20231114-C00192
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Figure US11814386-20231114-C00193
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Figure US11814386-20231114-C00194
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Figure US11814386-20231114-C00195
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Figure US11814386-20231114-C00196
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Figure US11814386-20231114-C00197
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Figure US11814386-20231114-C00198
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Figure US11814386-20231114-C00199
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Figure US11814386-20231114-C00200
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Figure US11814386-20231114-C00201
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Figure US11814386-20231114-C00202
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Figure US11814386-20231114-C00203
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Figure US11814386-20231114-C00204
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Figure US11814386-20231114-C00205
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Figure US11814386-20231114-C00206
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Figure US11814386-20231114-C00207
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Figure US11814386-20231114-C00208
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Figure US11814386-20231114-C00209
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Figure US11814386-20231114-C00210
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Figure US11814386-20231114-C00211
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Figure US11814386-20231114-C00212
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Figure US11814386-20231114-C00213
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Figure US11814386-20231114-C00214
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Figure US11814386-20231114-C00215
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Figure US11814386-20231114-C00216
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Figure US11814386-20231114-C00217
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Figure US11814386-20231114-C00218
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Figure US11814386-20231114-C00219
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Figure US11814386-20231114-C00220
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Figure US11814386-20231114-C00221
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Figure US11814386-20231114-C00222
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Figure US11814386-20231114-C00223
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Figure US11814386-20231114-C00224
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Figure US11814386-20231114-C00225
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Figure US11814386-20231114-C00226
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Figure US11814386-20231114-C00227
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Figure US11814386-20231114-C00228
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Figure US11814386-20231114-C00229
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Figure US11814386-20231114-C00230
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Figure US11814386-20231114-C00231
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Figure US11814386-20231114-C00232
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Figure US11814386-20231114-C00233
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Figure US11814386-20231114-C00234
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Figure US11814386-20231114-C00235
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Figure US11814386-20231114-C00236
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Figure US11814386-20231114-C00237
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Figure US11814386-20231114-C00238
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Figure US11814386-20231114-C00239
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Figure US11814386-20231114-C00240
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Figure US11814386-20231114-C00241
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Figure US11814386-20231114-C00242
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Figure US11814386-20231114-C00243
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Figure US11814386-20231114-C00244
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Figure US11814386-20231114-C00245
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Figure US11814386-20231114-C00246
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Figure US11814386-20231114-C00247
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Figure US11814386-20231114-C00248
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Figure US11814386-20231114-C00249
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Figure US11814386-20231114-C00250
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Figure US11814386-20231114-C00251
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Figure US11814386-20231114-C00252
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Figure US11814386-20231114-C00253
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Figure US11814386-20231114-C00254
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Figure US11814386-20231114-C00255
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Figure US11814386-20231114-C00256
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Figure US11814386-20231114-C00257
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Figure US11814386-20231114-C00258
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Figure US11814386-20231114-C00259
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Figure US11814386-20231114-C00260
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Figure US11814386-20231114-C00261
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Figure US11814386-20231114-C00262
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Figure US11814386-20231114-C00263
183
Figure US11814386-20231114-C00264
In some embodiments, a compound described herein is provided in non-salt form. In some embodiments, a compound described herein is provided as a pharmaceutically acceptable salt.
In another aspect, the disclosure relates to a compound, or a pharmaceutically acceptable salt thereof, prepared by a method comprising: preparing a compound of the present disclosure as a mixture of stereoisomers; separating the stereoisomers by chiral HPLC according to the procedure described in Example 2, Step 7; isolating one or more stereoisomers that are USP30 Inhibitor Compounds having an IC50 value of ≤1 μM as measured in a Ubiquitin-Rhodamine 110 Assay as described in Example 1; and optionally treating the isolated stereoisomer with an acid or base to afford a pharmaceutically acceptable salt thereof.
In some embodiments, the compound is the 1st eluting isomer. In some embodiments, the compound is the 2nd eluting isomer. In some embodiments, the compound is the 3rd eluting isomer. In some embodiments, the compound is the 4th eluting isomer. In some embodiments, the compound is the 5th, 6th, 7th, or 8th eluting isomer.
In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is a USP30 Inhibitor Compound having an IC50 value of ≤1 μM as measured in a Ubiquitin-Rhodamine 110 Assay as described in Example 1. In some embodiments, the IC50 value is ≤0.1 μM.
Pharmaceutical Compositions and Routes of Administration
The disclosure also relates to a pharmaceutical composition comprising one or more compounds provided herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the one or more compounds, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition is for use in a method of treating a neurodegenerative disorder, such as Parkinson's Disease.
The compounds and pharmaceutically acceptable salts disclosed herein may be administered via any mode of administration for therapeutic agents, consistent with conventional pharmaceutical practices. In some embodiments, the pharmaceutical compositions reported herein can be provided in a unit dosage form. In some embodiments, the pharmaceutical compositions reported herein can be provided in an oral dosage form. In some embodiments, the pharmaceutical compositions described herein can be provided in a solid oral dosage form, such as a tablet, capsule, powder, or cachet.
The pharmaceutical compositions described herein can be prepared according to conventional mixing, granulating or coating methods. For example, oral dosage forms (e.g., tablets) may be prepared by dry blending or dry granulation. The pharmaceutical compositions described herein can contain from about 0.1% to about 99%, from about 5% to about 90%, or from about 1% to about 20% of the compound or pharmaceutically acceptable salt by weight or volume. The pharmaceutically acceptable carriers employed in the pharmaceutical compositions described herein may include one or more pharmaceutical excipients, such as fillers, disintegrants, lubricants, glidants, anti-adherents, anti-statics, surfactants, or stabilizing additives. Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate, talc, sugar or lactose. With some drugs, the presence of such additives promotes the stability and dispersibility of the agent in solution. Suitable, but non-limiting, examples of stabilizing additives include gum acacia, gelatin, methyl cellulose, polyethylene glycol, carboxylic acids and salts thereof, and polylysine. In some embodiments, the stabilizing additives are gum acacia, gelatin and methyl cellulose. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pa.
The pharmaceutical compositions described herein may contain the compound or pharmaceutically acceptable salt in substantially pure form, such as at least 60% pure, more suitably at least 75% pure, preferably at least 85% pure and most preferably at least 98% pure (w/w).
The compounds and pharmaceutically acceptable salts described herein are preferably administered in a therapeutically effective amount (e.g., an amount having a suitable favorable therapeutic index). The amount and frequency of administration will be regulated according to the judgment of the attending clinician considering such factors as the age, gender, condition and size of the patient, as well as severity of the medical condition being treated; the route of administration; the renal or hepatic function of the patient; and the particular compound or pharmaceutically acceptable salt employed. A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition. For convenience, the total daily dosage may be divided and administered in portions during the day as required.
Uses of Compounds Disclosed Herein
The present disclosure also provides uses of compounds of formula (I). Compounds of formula (I) are useful in medicine. For examples, compounds and compositions described herein are inhibitors of USP30. Without wishing to be bound by any particular theory, such inhibition of USP30 can provide treatment of the symptoms and/or underlying causes of diseases or conditions associated with USP30 activity. In some embodiments, inhibitors of USP30 can be used to treat neurodegenerative and neurologic diseases or conditions, such as Parkinson's disease.
Provided herein are methods of treating a disease or disorder associated with a ubiquitin-specific protease (e.g., USP30), comprising administering to a patient in need thereof a therapeutically effective amount of a compound or composition provided herein. In some embodiments, the disease or disorder associated with a ubiquitin-specific protease (e.g., USP30) is a neurodegenerative disease or disorder (e.g., Parkinson's disease).
The present disclosure also provides methods of inhibiting a ubiquitin-specific protease (e.g., USP30) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound or composition provided herein.
The present disclosure also provides methods of treating a neurodegenerative disease or disorder (e.g., Parkinson's disease) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound or composition provided herein.
The present disclosure also provides compounds for use in method of inhibiting a ubiquitin-specific protease (e.g., USP30) in a patient in need thereof. In some embodiments, the present disclosure provides compounds for use in a method of treating a neurodegenerative disease or disorder (e.g., Parkinson's disease) in a patient in need thereof.
Synthesis of Compounds Disclosed Herein
The compounds and pharmaceutically acceptable salts disclosed herein may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthetic schemes. In the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis”, Third edition, Wiley, New York 1999). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art.
In general, the compounds of formula (I) can be synthesized by the methods outlined in Scheme 1, by the specific procedures discussed in Examples 2-4, and/or by methods otherwise known to one skilled in the art. The starting materials for the synthesis described in Scheme 1 are commercially available or can be prepared by methods known to one skilled in the art.
Figure US11814386-20231114-C00265
EXEMPLARY EMBODIMENTS
The following numbered embodiments, while non-limiting, are exemplary of certain aspects of the disclosure:
1. A compound of formula (I):
Figure US11814386-20231114-C00266
or a pharmaceutically acceptable salt thereof, wherein:
    • Ar1 is phenylene or 5-6 membered heteroarylene, wherein said phenylene or heteroarylene is substituted with m R1 groups;
    • Ar2 is phenylene or 5-6 membered heteroarylene, wherein said phenylene or heteroarylene is substituted with n R2 groups;
    • L is —O—, —S—, —NR3—, —C(R4)2—, —S(O)2—, or —S(O)—;
    • M is 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein said cycloalkyl, phenyl, or heteroaryl is substituted with p R5 groups;
    • each occurrence of R1, R2, and R5 is independently halo, cyano, NO2, oxo, hydroxyl, —R6, —OR6, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, —C1-C6 alkylene-R6, C1-C6 alkoxy, C1-C6 haloalkoxy, —C0-C3 alkylene-NR6R7, —C0-C3 alkylene-NR7R8, —C0-C3 alkylene-C(O)NR6R7, —C0-C3 alkylene-C(O)NR7R8, —C0-C3 alkylene-NR7C(O)R6, —C0-C3 alkylene-NR7C(O)R6, —C0-C3 alkylene-NR7S(O)2R6, —C0-C3 alkylene-C(O)R6, —C0-C3 alkylene-C(O)R7, —C0-C3 alkylene-SR6, —C0-C3 alkylene-S(O)R6, —C0-C3 alkylene-S(O)2R6, —C0-C3 alkylene-S(O)2R7, —C0-C3 alkylene-S(O)2NR6R7, —C0-C3 alkylene-S(O)2NR7R8, —C0-C3 alkylene-NR7C(O)NR8R9, —C0-C3 alkylene-NR7S(O)2NR8R9, —C0-C3 alkylene-C(O)OR7, —C0-C3 alkylene-C(O)OR6, —C0-C3 alkylene-OC(O)R7, —C0-C3 alkylene-OC(O)R6, —C0-C3 alkylene-NR7C(O)OR8, or —C0-C3 alkylene-NR7S(O)2R8;
    • R3 is H, C1-C6 alkyl, or C1-C6 haloalkyl;
    • each R4 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, or two R4 groups together with the carbon atom to which they are attached form a 3-6 membered cycloalkyl or heterocycloalkyl;
    • each R6 is independently 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl, or 3-8 membered cycloalkyl, wherein said heteroaryl, heterocycloalkyl, aryl, or cycloalkyl is optionally substituted with 1-5 substituents independently selected from the group consisting of halo, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl, 3-8 membered cycloalkyl, —NR10C(O)NR11R12, —NR10R11, —C(O)R10, —NR10C(O)R11, —NR10C(O)OR11, —S(O)2R10, —C(O)NR10R11, —C(O)OR10, —S(O)2NR10R11, —NR10S(O)2R11, —OR10, —OC(O)R10, —OS(O)2R10, —OC(O)NR10R11, —OC(O)OR10, —OS(O)2NR10R11, —C(O)R10, —C(O)NR10C(O)NR11R12, —C(O)NR10R11, —C(O)C(O)R10, —C(O)NR10C(O)R11, —C(O)NR10C(O)OR11, —C(O)S(O)2R10, —C(O)C(O)NR10R11, —C(O)C(O)OR10, —C(O)S(O)2NR10R11, —C(O)NR10S(O)2R11, —C1-C6 alkylene-R10, —C1-C6 alkylene-NR10C(O)NR11R12, —C1-C6 alkylene-NR10R11, —C1-C6 alkylene-C(O)R10, —C1-C6 alkylene-NR10C(O)R11, —C1-C6 alkylene-NR10C(O)OR11, —C1-C6 alkylene-S(O)2R10, —C1-C6 alkylene-C(O)NR10R11, —C1-C6 alkylene-C(O)OR10, —C1-C6 alkylene-S(O)2NR10R11, —C1-C6 alkylene-NR10S(O)2R11, —C1-C6 alkenylene-R10, —C1-C6 alkenylene-NR10C(O)NR11R12, —C1-C6 alkenylene-NR10R11, —C1-C6 alkenylene-C(O)R10, —C1-C6 alkenylene-NR10C(O)R11, —C1-C6 alkenylene-NR10C(O)OR11, —C1-C6 alkenylene-S(O)2R10, —C1-C6 alkenylene-C(O)NR10R11, —C1-C6 alkenylene-C(O)OR10, —C1-C6 alkenylene-S(O)2NR10R11, and —C1-C6 alkenylene-NR10S(O)2R1;
    • each R7, R8, and R9 is independently hydrogen or C1-C6 alkyl;
    • each R10, R11, and R12 is independently hydrogen, C1-C6 alkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl, or 3-8 membered cycloalkyl;
    • m is 0-4;
    • n is 0-4;
    • p is 0-4;
Ra, Rb, Rc, Rd, Re, Rf, Rg, and Rh are defined as follows:
    • (i) Ra and Rb form a C1-C4 alkylene group between the atoms to which they are attached, wherein said C1-C4 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Rc, Rd, Re, Rf, Rg, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
    • (ii) Ra and Re form a C1-C2 alkylene group between the atoms to which they are attached, wherein said C1-C2 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Rb, Rc, Rd, Rf, Rg, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
    • (iii) Ra and Rg form a C1-C3 alkylene group between the atoms to which they are attached, wherein said C1-C3 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Rb, Rc, Rd, Re, Rf, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
    • (iv) Rb and Rc form a C1-C4 alkylene group between the atoms to which they are attached, wherein said C1-C4 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Ra, Rd, Rc, Rf, Rg, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
    • (v) Rb and Re form a C1-C3 alkylene group between the atoms to which they are attached, wherein said C1-C4 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Ra, Rc, Rd, Rf, Rg, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
    • (vi) Rb and Rg form a C1-C4 alkylene group between the atoms to which they are attached, wherein said C1-C3 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Ra, Rc, Rd, Re, Rf, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
    • (vii) Rc and Rd together with the atom to which they are attached, form a 3-6 membered cycloalkyl or heterocycloalkyl, wherein said 3-6 membered cycloalkyl or heterocycloalkyl is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Ra, Rb, Re, Rf, Rg, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
    • (viii) Rc and Rd together form ═O; and Ra, Rb, Re, Rf, Rg, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
    • (ix) Rc and Re form a C1-C4 alkylene group between the atoms to which they are attached, wherein said C1-C4 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Ra, Rb, Rd, Rf, Rg, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
    • (x) Rc and Rg form a C1-C3 alkylene group between the atoms to which they are attached, wherein said C1-C3 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Ra, Rb, Rd, Re, Rf, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
    • (xi) Re and Rf together with the atom to which they are attached, form a 3-6 membered cycloalkyl or heterocycloalkyl, wherein said 3-6 membered cycloalkyl or heterocycloalkyl is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Ra, Rb, Rc, Rd, Rg, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
    • (xii) Re and Rf together form ═O; and Ra, Rb, Rc, Rd, Rg, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
    • (xiii) Re and Rg form a C1-C3 alkylene group between the atoms to which they are attached, wherein said C1-C3 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Ra, Rb, Rc, Rd, Rf, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
    • (xiv) Rg and Rh together with the atom to which they are attached, form a 3-6 membered cycloalkyl or heterocycloalkyl, wherein said 3-6 membered cycloalkyl or heterocycloalkyl is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Ra, Rb, Rc, Rd, Re, and Rf are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
    • (xv) Rg and Rh together form ═O; and Ra, Rb, Rc, Rd, Re, and Rf are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl.
      2. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein Rc and Rg form a C1-C3 alkylene group between the atoms to which they are attached, wherein said C1-C3 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Ra, Rb, Rd, Re, Rf, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl.
      3. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein Rb and Rc form a C1-C4 alkylene group between the atoms to which they are attached, wherein said C1-C4 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Ra, Rd, Re, Rf, Rg, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl.
      4. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein Rc and Rd together with the atom to which they are attached, form a 3-6 membered cycloalkyl or heterocycloalkyl, wherein said 3-6 membered cycloalkyl or heterocycloalkyl is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Ra, Rb, Re, Rf, Rg, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl.
      5. The compound of embodiment 1, wherein the compound has formula (I-A):
Figure US11814386-20231114-C00267
or a pharmaceutically acceptable salt thereof, wherein:
    • X1 is C or N;
    • X2 is CH, CR1, O, S, N, NH, or NR1;
    • X3 is CH, CR1, O, S, N, NH, or NR1;
    • X4 is C or N;
    • X5 is a bond, CH, CR1, O, S, N, NH, or NR1;
    • X6 is CH, CR1, O, S, N, NH, or NR1;
    • Y1 is C or N;
    • Y2 is C or N;
    • Y3 is CH, CR2, O, S, N, NH, or NR2;
    • Y4 is a bond, CH, CR2, O, S, N, NH, or NR2;
    • Y5 is CH, CR2, O, S, N, NH, or NR2;
    • Y6 is CH, CR2, O, S, N, NH, or NR2;
Ra, Rb, Rc, Rd, Re, Rf, Rg, and Rh are defined as follows:
    • (ii) Ra and Rc form a C1-C2 alkylene group between the atoms to which they are attached, wherein said C1-C2 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Rb, Rc, Rd, Rf, Rg, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
    • (iv) Rb and Re form a C1-C4 alkylene group between the atoms to which they are attached, wherein said C1-C4 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Ra, Rd, Re, Rf, Rg, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
    • (vii) Rc and Rd together with the atom to which they are attached, form a 3-6 membered cycloalkyl or heterocycloalkyl, wherein said 3-6 membered cycloalkyl or heterocycloalkyl is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Ra, Rb, Re, Rf, Rg, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
    • (viii) Re and Rd together form ═O; and Ra, Rb, Re, Rf, Rg, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
    • (ix) Rc and Re form a C1-C4 alkylene group between the atoms to which they are attached, wherein said C1-C4 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Ra, Rb, Rd, Rf, Rg, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
    • (x) Rc and Rg form a C1-C3 alkylene group between the atoms to which they are attached, wherein said C1-C3 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Ra, Rb, Rd, Re, Rf, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
    • (xi) Re and Rf together with the atom to which they are attached, form a 3-6 membered cycloalkyl or heterocycloalkyl, wherein said 3-6 membered cycloalkyl or heterocycloalkyl is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Ra, Rb, Rc, Rd, Rg, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
    • (xiii) Re and Rg form a C1-C3 alkylene group between the atoms to which they are attached, wherein said C1-C3 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Ra, Rb, Rc, Rd, Rf, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
    • (xv) Rg and Rh together form ═O; and Ra, Rb, Rc, Rd, Re, and Rf are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl.
      6. The compound of embodiment 5, or a pharmaceutically acceptable salt thereof, wherein Rc and Rg form a C1-C3 alkylene group between the atoms to which they are attached, wherein said C1-C3 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Ra, Rb, Rd, Re, Rf, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl.
      7. The compound of embodiment 5, or a pharmaceutically acceptable salt thereof, wherein Rb and Rc form a C1-C4 alkylene group between the atoms to which they are attached, wherein said C1-C4 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Ra, Rd, Re, Rf, Rg, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl.
      8. The compound of embodiment 5, or a pharmaceutically acceptable salt thereof, wherein Rc and Rd together with the atom to which they are attached, form a 3-6 membered cycloalkyl or heterocycloalkyl, wherein said 3-6 membered cycloalkyl or heterocycloalkyl is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Ra, Rb, Re, Rf, Rg, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl.
      9. The compound of any one of embodiments 5-8, or a pharmaceutically acceptable salt thereof, wherein X1 is C; X2 is N; X3 is NH; X4 is C; X5 is a bond; and X6 is CH.
      10. The compound of any one of embodiments 5-9, or a pharmaceutically acceptable salt thereof, wherein Y1 is C; Y2 is C; Y3 is CH; Y4 is CH; Y5 is CH; and Y6 is CH.
      11. The compound of any one of embodiments 5-10, or a pharmaceutically acceptable salt thereof, wherein L is O.
      12. The compound of any one of embodiments 5-11, or a pharmaceutically acceptable salt thereof, wherein M is phenyl substituted with p R5 groups.
      13. The compound of embodiment 1, wherein the compound has formula (I-B):
Figure US11814386-20231114-C00268
or a pharmaceutically acceptable salt thereof, wherein:
    • X1 is C or N;
    • X2 is CH, CR1, O, S, N, NH, or NR1;
    • X3 is CH, CR1, O, S, N, NH, or NR1;
    • X4 is C or N;
    • X6 is CH, CR1, O, S, N, NH, or NR1;
    • Y3 is CH, CR2, or N;
    • Y4 is CH, CR2, or N;
    • Y5 is CH, CR2, or N;
    • Y6 is CH, CR2, or N;
Ra, Rb, Rc, Rd, Re, Rf, Rg, and Rh are defined as follows:
    • (ii) Ra and Re form a C1-C2 alkylene group between the atoms to which they are attached, wherein said C1-C2 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Rb, Rc, Rd, Rf, Rg, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
    • (iv) Rb and Rc form a C1-C4 alkylene group between the atoms to which they are attached, wherein said C1-C4 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Ra, Rd, Re, Rf, Rg, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
    • (vii) Re and Rd together with the atom to which they are attached, form a 3-6 membered cycloalkyl or heterocycloalkyl, wherein said 3-6 membered cycloalkyl or heterocycloalkyl is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Ra, Rb, Re, Rf, Rg, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
    • (viii) Rc and Rd together form ═O; and Ra, Rb, Re, Rf, Rg, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
    • (ix) Rc and Re form a C1-C4 alkylene group between the atoms to which they are attached, wherein said C1-C4 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Ra, Rb, Rd, Rf, Rg, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
    • (x) Rc and Rg form a C1-C3 alkylene group between the atoms to which they are attached, wherein said C1-C3 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Ra, Rb, Rd, Re, Rf, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
    • (xi) Re and Rf together with the atom to which they are attached, form a 3-6 membered cycloalkyl or heterocycloalkyl, wherein said 3-6 membered cycloalkyl or heterocycloalkyl is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Ra, Rb, Rc, Rd, Rg, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
    • (xiii) Re and Rg form a C1-C3 alkylene group between the atoms to which they are attached, wherein said C1-C3 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Ra, Rb, Rc, Rd, Rf, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
    • (xv) Rg and Rh together form ═O; and Ra, Rb, Rc, Rd, Re, and Rf are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl.
      14. The compound of embodiment 13, or a pharmaceutically acceptable salt thereof, wherein Rc and Rg form a C1-C3 alkylene group between the atoms to which they are attached, wherein said C1-C3 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Ra, Rb, Rd, Re, Rf, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl.
      15. The compound of embodiment 13, or a pharmaceutically acceptable salt thereof, wherein Rb and Rc form a C1-C4 alkylene group between the atoms to which they are attached, wherein said C1-C4 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Ra, Rd, Re, Rf, Rg, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl.
      16. The compound of embodiment 13, or a pharmaceutically acceptable salt thereof, wherein Rc and Rd together with the atom to which they are attached, form a 3-6 membered cycloalkyl or heterocycloalkyl, wherein said 3-6 membered cycloalkyl or heterocycloalkyl is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Ra, Rb, Re, Rf, Rg, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl.
      17. The compound of any one of embodiments 13-16, or a pharmaceutically acceptable salt thereof, wherein X1 is C; X2 is N; X3 is NH; X4 is C; and X6 is CH.
      18. The compound of any one of embodiments 13-17, or a pharmaceutically acceptable salt thereof, wherein Y1 is C; Y2 is C; Y3 is CH; Y4 is CH; Y5 is CH; and Y6 is CH.
      19. The compound of any one of embodiments 13-18, or a pharmaceutically acceptable salt thereof, wherein L is O.
      20. The compound of any one of embodiments 13-19, or a pharmaceutically acceptable salt thereof, wherein M is phenyl substituted with p R5 groups.
      21. The compound of embodiment 1, wherein the compound has formula (I-C):
Figure US11814386-20231114-C00269
or a pharmaceutically acceptable salt thereof, wherein:
Ra, Rb, Rc, Rd, Re, Rf, Rg, and Rh are defined as follows:
    • (ii) Ra and Re form a C1-C2 alkylene group between the atoms to which they are attached; and Rb, Rc, Rd, Rf, Rg, and Rh are each hydrogen; or
    • (iv) Rb and Rc form a C1-C4 alkylene group between the atoms to which they are attached; and Ra, Rd, Re, Rf, Rg, and Rh are each hydrogen; or
    • (vii) Rc and Rd together with the atom to which they are attached, form a 3-6 membered cycloalkyl or heterocycloalkyl; and Ra, Rb, Re, Rf, Rg, and Rh are each hydrogen; or
    • (viii) Rc and Rd together form ═O; and Ra, Rb, Rc, Rf, Rg, and Rh are each hydrogen; or
    • (ix) Rc and Re form a C1-C4 alkylene group between the atoms to which they are attached; and Ra, Rb, Rd, Rf, Rg, and Rh are each hydrogen; or
    • (x) Rc and Rg form a C1-C3 alkylene group between the atoms to which they are attached; and Ra, Rb, Rd, Re, Rf, and Rh are each hydrogen; or
    • (xi) Re and Rf together with the atom to which they are attached, form a 3-6 membered cycloalkyl or heterocycloalkyl; and Ra, Rb, Rc, Rd, Rg, and Rh are each hydrogen; or
    • (xiii) Re and Rg form a C1-C3 alkylene group between the atoms to which they are attached; and Ra, Rb, Rc, Rd, Rf, and Rh are each independently hydrogen or
    • (xv) Rg and Rh together form ═O; and Ra, Rb, Rc, Rd, Re, and Rf are each hydrogen.
      22. The compound of embodiment 21, or a pharmaceutically acceptable salt thereof, wherein Ra, Rh, Rc, Rd, Re, Rf, Rg, and Rh are defined as follows:
    • (ii) Ra and Rc form a C1-C2 alkylene group between the atoms to which they are attached; and Rb, Rc, Rd, Rf, Rg, and Rh are each hydrogen; or
    • (iv) Rb and Rc form a C1-C3 alkylene group between the atoms to which they are attached; and Ra, Rd, Re, Rf, Rg, and Rh are each hydrogen; or
    • (vii) Rc and Rd together with the atom to which they are attached, form a 3-membered cycloalkyl or a 4-membered heterocycloalkyl; and Ra, Rb, Re, Rf, Rg, and Rh are each hydrogen; or
    • (viii) Rc and Rd together form ═O; and Ra, Rb, Re, Rf, Rg, and Rh are each hydrogen; or
    • (ix) Rc and Rg form a C1 alkylene group between the atoms to which they are attached; and Ra, Rb, Rd, Rf, Rg, and Rh are each hydrogen; or
    • (x) Rc and Rg form a C1-C2 alkylene group between the atoms to which they are attached; and Ra, Rb, Rd, Re, Rf, and Rh are each hydrogen; or
    • (xi) Re and Rf together with the atom to which they are attached, form a 4-membered heterocycloalkyl; and Ra, Rb, Rc, Rd, Rg, and Rh are each hydrogen; or
    • (xiii) Re and Rg form a C2 alkylene group between the atoms to which they are attached; and Ra, Rb, Rc, Rd, Rf, and Rh are each independently hydrogen or
    • (xv) Rg and Rh together form ═O; and Ra, Rb, Rc, Rd, Re, and Rf are each hydrogen.
      23. The compound of embodiment 22, or a pharmaceutically acceptable salt thereof, wherein Rc and Rg form a C1-C2 alkylene group between the atoms to which they are attached; and Ra, Rb, Rd, Re, Rf, and Rh are each hydrogen.
      24. The compound of embodiment 22, or a pharmaceutically acceptable salt thereof, wherein Rb and Rc form a C1-C3 alkylene group between the atoms to which they are attached; and Ra, Rd, Rc, Rf, Rg, and Rh are each hydrogen.
      25. The compound of embodiment 22, or a pharmaceutically acceptable salt thereof, wherein Rc and Rd together with the atom to which they are attached, form a 3-membered cycloalkyl or a 4-membered heterocycloalkyl; and Ra, Rb, Re, Rf, Rg, and Rh are each hydrogen.
      26. The compound of any one of embodiments 21-25, or a pharmaceutically acceptable salt thereof, wherein n and p are 0.
      27. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from Table 1.
      28. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from Table 2.
      29. The compound of any one of embodiments 1-28, or a pharmaceutically acceptable salt thereof, that is a USP30 Inhibitor Compound having an IC50 value of ≤1 μM as measured in a Ubiquitin-Rhodamine 110 Assay as described in Example 1.
      30. The compound of embodiment 29, or a pharmaceutically acceptable salt thereof, wherein the IC50 value is ≤0.1 μM.
      31. A compound of formula (I-C)
Figure US11814386-20231114-C00270
or a pharmaceutically acceptable salt thereof, that is a USP30 Inhibitor Compound having an IC50 value of ≤1 μM and >0.001 μM as measured in a Ubiquitin-Rhodamine 110 Assay as described in Example 1, wherein:
    • each occurrence of R2 and R5 is independently halo, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 haloalkyl, and C1-C6 hydroxyalkyl;
    • n is 0-4;
    • p is 0-4;
    • Rh is hydrogen;
Ra, Rb, Rc, Rd, Re, Rf, and Rg are defined as follows:
    • (ii) Ra and Re form a C1-C2 alkylene group between the atoms to which they are attached; and Rb, Rc, Rd, Rf, and Rg are each hydrogen; or
    • (iv) Rb and Re form a C1-C2 alkylene group between the atoms to which they are attached; and Ra, Rc, Rd, Rf, and Rg are each hydrogen; or
    • (vii) Rc and Rd together with the atom to which they are attached, form a 3 membered cycloalkyl; and Ra, Rb, Re, Rf, and Rg are each hydrogen; or
    • (x) Rc and Rg form a C1-C2 alkylene group between the atoms to which they are attached; and Ra, Rb, Rd, Re, and Rf are each hydrogen; or
    • (xi) Re and Rf together with the atom to which they are attached, form a 4 membered heterocycloalkyl; and Ra, Rb, Rc, Rd, and Rg are each hydrogen; or
    • (xiii) Re and Rg form a C2 alkylene group between the atoms to which they are attached; and Ra, Rb, Rc, Rd, and Rf are each independently hydrogen.
      32. The compound of embodiment 31, or a pharmaceutically acceptable salt thereof, wherein the compound has the following formula
Figure US11814386-20231114-C00271
33. The compound of embodiment 31, or a pharmaceutically acceptable salt thereof, wherein the compound has the following formula
Figure US11814386-20231114-C00272
34. The compound of embodiment 31, or a pharmaceutically acceptable salt thereof, wherein the compound has the following formula
Figure US11814386-20231114-C00273
35. The compound of embodiment 31, or a pharmaceutically acceptable salt thereof, wherein the compound has the following formula
Figure US11814386-20231114-C00274
36. The compound of any one of embodiments 31-35, or a pharmaceutically acceptable salt thereof, wherein n and p are 0.
37. A pharmaceutical composition comprising the compound of any one of embodiments 1-36, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
38. A method of inhibiting a ubiquitin-specific protease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the compound of any one of embodiments 1-36, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 37.
39. The method of embodiment 38, wherein the ubiquitin-specific protease is USP30.
40. A method of treating a neurodegenerative disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the compound of any one of embodiments 1-36, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 37.
41. The method of embodiment 40, wherein the neurodegenerative disorder is Parkinson's Disease.
42. A compound of any one of embodiments 1-36, or a pharmaceutically acceptable salt thereof, for use in a method of inhibiting a ubiquitin-specific protease in a patient in need thereof.
43. The compound or pharmaceutically acceptable salt for use of embodiment 42, wherein the ubiquitin-specific protease is USP30.
44. A compound of any one of embodiments 1-36, or a pharmaceutically acceptable salt thereof, for use in a method of treating a neurodegenerative disorder in a patient in need thereof.
45. The compound or pharmaceutically acceptable salt for use of embodiment 44, wherein the neurodegenerative disorder is Parkinson's Disease.
46. A USP30 Inhibitor Compound of the formula:
Figure US11814386-20231114-C00275
or a pharmaceutically acceptable salt thereof, wherein:
    • each occurrence of R2 and R5 is independently halo, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 haloalkyl, or C1-C6 hydroxyalkyl;
    • n is 0-4;
    • p is 0-4.
      47. The compound of any one of embodiments 1-36 or 44-46, having an IC50 value of ≤0.5 μM and >0.001 μM as measured in a Ubiquitin-Rhodamine 110 Assay as described in Example 1
      48. The compound of embodiment 47, having an IC50 value of ≤0.1 μM and >0.001 μM as measured in a Ubiquitin-Rhodamine 110 Assay as described in Example 1.
      49. A USP30 Inhibitor Compound as disclosed and provided herein.
      50. The USP30 Inhibitor Compound of embodiment 49, having an IC50 value of ≤1 μM and >0.001 μM as measured in a Ubiquitin-Rhodamine 110 Assay as described in Example 1.
EXAMPLES
General Methods
All solvents used were commercially available and were used without further purification. Reactions were typically run using anhydrous solvents under an inert atmosphere of nitrogen.
Proton NMR spectra were recorded using a Bruker Plus 400 NMR Spectrometer. The deuterated solvent (DMSO-d6) typically contained 0.03% to 0.05% v/v tetramethylsilane, which was used as the reference signal (set at δ 0.00 for 1H).
LCMS analyses were performed on a SHIMADZU LCMS consisting of an UFLC 20-AD and LCMS 2020 MS detector. The column used was a Shim-pack XR-ODS, 2.2 μm, 3.0×50 mm. The instrument uses reverse-phase conditions (acetonitrile/water, containing 0.05% ammonia).
Abbreviations
Unless otherwise noted, or where the context dictates otherwise, the following abbreviations shall be understood to have the following meanings:
    • δ chemical shift
    • ACN Acetonitrile
    • DIEA N,N-Diisopropylethylamine
    • DMF N,N-Dimethylformamide
    • DCM Dichloromethane or methylene chloride
    • h hour
    • 1H NMR proton nuclear magnetic resonance
    • HATU 2-(3H-[1,2,3]Triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate
    • HPLC high performance liquid chromatography
    • Hz Hertz
    • LCMS liquid chromatography/mass spectrometry
    • min minutes
    • MS mass spectrometry
    • ppm parts per million
    • RT retention time
    • SEMCl 2-chloromethyl 2-(trimethylsilyl)ethyl ether
    • TFA Trifluoroacetic acid
    • THF Tetrahydrofuran
    • XPhos-Pd Chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)
    • XPhos-Pd-G3 (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate
Example 1: Ubiquitin-Rhodamine 110 Assay for USP30 Activity
The assay was performed in a final volume of 9 μL in assay buffer containing 20 mM Tris-HCl (pH 8.0, (IM Tris-HCl, pH 8.0 solution; Corning 46-031-CM)), 1 mM GSH (L-glutathione reduced, Sigma-Aldrich, G4251-100G), 0.03% BGG (0.22 μM filtered, Sigma, G7516-25G), and 0.01% Triton X-100 (Sigma, T9284-10L). Nanoliter quantities of 10-point, 3-fold serial dilution in DMSO were pre-dispensed into 1536 assay plates (Corning, #3724BC) for a final test concentration of 25 μM to 1.3 nM, top to lowest dose, respectively. Concentration and incubation times were optimized for the maximal signal-to-background while maintaining initial velocity conditions at a fixed substrate concentration. The final concentration of USP30 (human recombinant USP30, Boston Biochem, cat. #E-582) in the assay was 0.2 nM. Final substrate (Ub-Rh110; Ubiquitin-Rhodamine 110, UbiQ-126) concentration was 25 nM with [Ub-Rh110]<<Km. 3 μL of 2×USP30 was added to assay plates (pre-stamped with compound), preincubated for 30 minutes and then treated with 3 μL of 2×Ub-Rh110. Plates were incubated for 30 minutes at room temperature before addition of 3 μL of stop solution (final concentration of 10 mM citric acid (Sigma, 251275-500G)). Fluorescence was read on the Envision (excitation at 485 nm and emission at 535 nm; Perkin Elmer) or on the PheraSTAR (excitation at 485 nm and emission at 535 nm; BMG Labtech) fluorescence reader.
For all assay formats, data were reported as percent inhibition compared with control wells based on the following equation: % inh=1−((FLU−AveLow)/(AveHigh−AveLow)) where FLU=measured Fluorescence, AveLow=average Fluorescence of no enzyme control (n=16), and AveHigh=average Fluorescence of DMSO control (n=16). IC50 values were determined by curve fitting of the standard 4 parameter logistic fitting algorithm included in the Activity Base software package: IDBS XE Designer Model205. Data is fitted using the Levenburg Marquardt algorithm.
The calculated IC50 values of the compounds described herein are reported in Table 3, where A represents an IC50 of <0.1 μM, B represents an IC50 of 0.1 to 1.0 μM, and C represents an IC50 of >1.0 μM. Compounds in the USP30 biochemical assay were deemed active if the IC50 was ≤1 μM.
TABLE 3
IC50 Values of Compounds in
Ubiquitin-Rhodamine 110 Assay
Compound IC50 (μM)
 1-a B
 1b A
 2-a A
 2-b C
 3-a B
 3-b A
 4-a B
 4-b B
 5-a A
 5-b B
 6-a A
 6-b B
 7-a A
 7-b B
 8-a B
 8-b B
 9-a C
 9-b C
13-a A
13-b A
20-a A
20-b A
Example 2: Preparation of (1S,5R)-2-(5-(2-phenoxyphenyl)-1H-pyrazole-3-carbonyl)-2,6-diazabicyclo[3.2.1]octane-6-carbonitrile (1-a) and (1R,5S)-2-(5-(2-phenoxyphenyl)-1H-pyrazole-3-carbonyl)-2,6-diazabicyclo[3.2.1]octane-6-carbonitrile (1-b)
Figure US11814386-20231114-C00276
Compounds 1-a and 1-b were prepared by the following route:
Figure US11814386-20231114-C00277
Step 1. Methyl 5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carboxylate
2-Chloromethyl 2-(trimethylsilyl)ethyl ether (12.3 mL, 69.5 mmol) was added to a mixture of methyl 5-bromo-1H-pyrazole-3-carboxylate (5.00 g, 23.2 mmol) and K2CO3 (18.0 g, 130 mmol) in DMF (50 mL) at 0° C. in an ice/water bath. The resulting solution was stirred for 14 h at 25° C. The reaction was quenched by the addition of water (100 mL). The resulting mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 15:1 petroleum ether/ethyl acetate) to afford methyl 5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carboxylate as a yellow oil (6.20 g, 79%). LCMS (ES, m/z) 335, 337 [M+H]+.
Step 2. Methyl 5-(2-phenoxyphenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carboxylate
A solution of methyl 5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carboxylate (6.20 g, 18.4 mmol), (2-phenoxyphenyl)boronic acid (4.96 g, 23.2 mmol), XPhos-Pd (2.90 g, 3.68 mmol) and K3PO4 (11.7 g, 55.2 mmol) in dioxane (120 mL) and H2O (24 mL) was stirred for 15 h at 100° C. in an oil bath. After cooling to 25° C., the solids were filtered out. The filtrate was concentrated under vacuum. The residue was diluted with water (50 mL). The resulting mixture was extracted with ethyl acetate (3×50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by reverse phase chromatography (Column: XBridge Shield RP18 OBD Column, 5 μm, 30×150 mm; Mobile phase, A: water (containing 10 mmol/L NH4HCO3) and B: ACN (5% B to 72% over 20 min); Detector: UV: 220 and 254 nm) to afford methyl 5-(2-phenoxyphenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carboxylate as a yellow solid (3.20 g, 41%). LCMS (ES, m/z) 425 [M+H]+.
Step 3. 5-(2-Phenoxyphenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carboxylic acid
A solution of methyl 5-(2-phenoxyphenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carboxylate (1.40 g, 3.30 mmol) and LiOH (0.810 g, 33.8 mmol) in THF (60 mL) and H2O (15 mL) was stirred for 4 h at 50° C. The mixture was allowed to cool to 25° C. and concentrated under vacuum. The pH value of the residue was adjusted to 5-6 with 3 N hydrochloric acid. The solids were collected by filtration and dried in an oven to afford 5-(2-phenoxyphenyl)-1-[[2-(trimethylsilyl)ethoxy] methyl]-1H-pyrazole-3-carboxylic acid as an off-white solid (1.05 g, 78%). LCMS (ES, m/z) 411 [M+H]+.
Step 4. tert-butyl 2-[5-(2-phenoxyphenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carbonyl]-2,6-diazabicyclo[3.2.1]octane-6-carboxylate
A solution of 5-(2-phenoxyphenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carboxylic acid (150 mg, 0.366 mmol), HATU (210 mg, 0.541 mmol), tert-butyl 2,6-diazabicyclo[3.2.1]octane-6-carboxylate (75.0 mg, 0.346 mmol) and DIEA (0.2 mL, 1.40 mmol) in DMF (2 mL) was stirred for 3 h at 25° C. The reaction was quenched by the addition of water (10 mL). The resulting mixture was extracted with ethyl acetate (3×20 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 1/1 petroleum ether/ethyl acetate) to afford tert-butyl 2-[5-(2-phenoxyphenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carbonyl]-2,6-diazabicyclo[3.2.1]octane-6-carboxylate as a white solid (100 mg, 45%). LCMS (ES, m/z): 605 [M+H]+.
Step 5. 2-[5-(2-phenoxyphenyl)-1H-pyrazole-3-carbonyl]-2,6-diazabicyclo[3.2.1]octane 2,2,2-trifluoroacetate
A solution of tert-butyl 2-[5-(2-phenoxyphenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carbonyl]-2,6-diazabicyclo[3.2.1]octane-6-carboxylate (100 mg, 0.157 mmol) and TFA (1 mL) in DCM (2 mL) was stirred for 2 h at 25° C. The resulting mixture was concentrated under vacuum to afford 2-[5-(2-phenoxyphenyl)-1H-pyrazole-3-carbonyl]-2,6-diazabicyclo[3.2.1]octane 2,2,2-trifluoroacetate as a colorless oil (110 mg, crude). LCMS (ES, m/z): 375 [M+H]+.
Step 6. 2-[5-(2-phenoxyphenyl)-1H-pyrazole-3-carbonyl]-2,6-diazabicyclo[3.2.1]octane-6-carbonitrile
Cyanogen bromide (17.8 mg, 0.170 mmol) was added to a 0° C. mixture of 2-[5-(2-phenoxyphenyl)-1H-pyrazole-3-carbonyl]-2,6-diazabicyclo[3.2.1]octane 2,2,2-trifluoroacetate (80.0 mg, 0.170 mmol) and NaHCO3 (82.0 mg, 0.957 mmol) in DMF (2 mL). The resulting mixture stirred for 16 h at 25° C. The reaction was quenched by the addition of water (10 mL). The resulting mixture was extracted with ethyl acetate (3×20 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 5 μm, 19×150 mm; Mobile Phase A: water (containing 10 mmol/L NH4HCO3) and B: CH3CN (30% to 55% in 8 min); Flow rate: 25 mL/min; Detector: 220 nm) to afford 2-[5-(2-phenoxyphenyl)-1H-pyrazole-3-carbonyl]-2,6-diazabicyclo[3.2.1]octane-6-carbonitrile as a white solid (40.0 mg, 59%). LCMS (ES, m/z): 400 [M+H]+.
Step 7. (1S,5R)-2-(5-(2-phenoxyphenyl)-1H-pyrazole-3-carbonyl)-2,6-diazabicyclo[3.2.1]octane-6-carbonitrile and (1R,5S)-2-(5-(2-phenoxyphenyl)-1H-pyrazole-3-carbonyl)-2,6-diazabicyclo[3.2.1]octane-6-carbonitrile
2-[5-(2-Phenoxyphenyl)-1H-pyrazole-3-carbonyl]-2,6-diazabicyclo[3.2.1]octane-6-carbonitrile (40.0 mg, 0.100 mmol) was separated by chiral-HPLC (Column: CHIRAL ART Cellulose-SB, 2×25 cm, 5 um; Mobile Phase A: n-hexane and B: EtOH (hold 50% in 15 min); Flow rate: 20 mL/min; Detector: 254/220 nm; RT1: 8.911 min and RT2: 11.119 min). The first eluting isomer (RT1=8.911 min) was collected and concentrated under vacuum, then lyophilized to obtain a compound for which the absolute stereochemistry was arbitrarily assigned as (1S,5R)-2-(5-(2-phenoxyphenyl)-1H-pyrazole-3-carbonyl)-2,6-diazabicyclo[3.2.1]octane-6-carbonitrile (1-a) as a white solid (13.8 mg, 35%). LCMS (ES, m/z): 400 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz) δ (ppm): 13.63 (br s, 1H), 7.86-7.85 (m, 1H), 7.44-7.29 (m, 4H), 7.13-6.90 (m, 5H), 5.49-5.18 (m, 1H), 4.65-4.31 (m, 1H), 4.18-4.17 (m, 1H), 3.65-3.46 (m, 3H), 3.08-3.03 (m, 1H), 1.86-1.72 (m, 4H). The second eluting isomer (RT2=11.119 min) was collected and concentrated under vacuum, then lyophilized to obtain a compound for which the absolute stereochemistry was arbitrarily assigned as (1R,5S)-2-(5-(2-phenoxyphenyl)-1H-pyrazole-3-carbonyl)-2,6-diazabicyclo[3.2.1]octane-6-carbonitrile (1-b) as a white solid (14.8 mg, 37%). LCMS (ES, m/z): 400 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz) δ (ppm): 13.63 (br s, 1H), 7.88-7.85 (m, 1H), 7.44-7.29 (m, 4H), 7.14-6.90 (m, 5H), 5.48-5.17 (m, 1H), 4.65-4.31 (m, 1H), 4.18-4.17 (m, 1H), 3.65-3.48 (m, 3H), 3.08-3.03 (m, 1H), 1.86-1.72 (m, 4H).
The compounds set forth in Table 4 were prepared by methods analogous to the preparation of compounds 1-a and 1-b. Each pair of compounds listed in Table 4 (i.e., compounds 2-a and 2-b, compounds 3-a and 3-b, etc.) was obtained as a racemic mixture, and were then separated by chiral HPLC according to the procedure described in Example 2, Step 7, to obtain the individual compounds in substantially enantiomerically pure form. The first and second eluting enantiomer of each enantiomer pair is identified in Table 4. The absolute stereochemistry of each enantiomer was arbitrarily assigned.
TABLE 4
Additional Compounds Prepared By Analogous Methods
MS
(ESI,
Cmpd IUPAC m/z) 1H-NMR
No. Structure name [M + H]+ δ (ppm)
2-a
Figure US11814386-20231114-C00278
 		N- ((1S,4S,7S)-2- cyano-2- azabicyclo[2.2.1] heptan-7- yl)-5-(2- phenoxyphe- nyl)-1H- pyrazole-3- carboxamide 400 1HNMR (DMSO-d6, 400 MHz) δ (ppm): 13.7-13.6 (m, 1H), 8.42-8.15 (m, 1H), 8.04-7.85(m, 1H), 7.42-7.29 (m, 4H), 7.15-7.10 (m, 1H), 7.02-6.95 (m, 4H), 4.06-4.04 (m, 1H), 3.84-3.82 (m, 1H), 3.52-3.49 (m, 1H), 3.10-3.06 (m, 1H), 2.67-2.62 (m, 1H), 1.97-1.88 (m, 1H), 1.84-1.71 (m, 2H), 1.54-1.48 (m, 1H).
2-b
Figure US11814386-20231114-C00279
 		N- ((1R,4R,7R)- 2-cyano-2- azabicyclo[2.2.1] heptan-7- yl)-5-(2- phenoxyphe- nyl)-1H- pyrazole-3- carboxamide 400 1HNMR (DMSO-d6, 400 MHz) δ (ppm): 13.8-13.6 (m, 1H), 8.57-8.15 (m, 1H), 8.02-7.86 (m, 1H), 7.40-7.22 (m, 4H), 7.15-7.11 (m, 1H), 7.01-6.97 (m, 4H), 4.06-4.04 (m, 1H), 3.83-3.81 (m, 1H), 3.53-3.50 (m, 1H), 3.09-3.06 (m, 1H), 2.71-2.60 (m, 1H), 1.97-1.88 (m, 1H), 1.84-1.71 (m, 2H), 1.54-1.48 (m, 1H).
4-a
Figure US11814386-20231114-C00280
 		(1S,4S)-5-(5- (2- phenoxyphe- nyl)-1H- pyrazole-3- carbonyl)-2,5- diazabicyclo [2.2.1]heptane- 2-carbonitrile 386 1HNMR (DMSO-d6, 400 MHz) δ (ppm): 13.7 (br s, 1H), 7.91-7.89 (m, 1H), 7.44-7.37(m, 3H), 7.32-7.29 (m, 1H), 7.15-7.12 (m, 1H), 7.03-6.99 (m, 4H), 5.50-5.40 (m, 0.5H), 4.87-4.86 (m, 0.5H), 4.46-4.43 (m, 1H), 4.06-3.88 (m, 1H), 3.65-3.51 (m, 2H), 3.36-3.34 (m, 1H), 1.99-1.85 (m, 2H).
4-b
Figure US11814386-20231114-C00281
 		(1R,4R)-5-(5- (2- phenoxyphe- nyl)-1H- pyrazole-3- carbonyl)-2,5- diazabicyclo [2.2.1]heptane- 2-carbonitrile 386 1HNMR (DMSO-d6, 400 MHz) δ (ppm): 13.7 (br s, 1H), 7.91-7.89 (m, 1H), 7.44-7.37(m, 3H), 7.32-7.29 (m, 1H), 7.15-7.12 (m, 1H), 7.03-6.99 (m, 4H), 5.50-5.40 (m, 0.5H), 4.87-4.86 (m, 0.5H), 4.46-4.43 (m, 1H), 3.99-3.88 (m, 1H), 3.65-3.51 (m, 2H), 3.44-3.34 (m, 1H), 1.99-1.81 (m, 2H).
5-a
Figure US11814386-20231114-C00282
 		(S)-N-(5- cyano-5- azaspiro[2.4] heptan-7-yl)-5- (2- phenoxyphe- nyl)-1H- pyrazole-3- carboxamide 400 1HNMR (DMSO-d6, 400 MHz) δ (ppm): 13.6 (br s, 1H), 8.41-8.38 (m, 1H), 7.92-7.85(m, 1H), 7.41-7.29 (m, 4H), 7.15-7.12 (m, 1H), 7.02-6.91 (m, 4H), 4.25-4.20 (m, 1H), 3.82-3.78 (m, 1H), 3.68-3.65 (m, 1H), 3.52-3.44 (m, 1H), 3.25-3.24 (m, 1H), 0.80-0.59 (m, 4H).
5-b
Figure US11814386-20231114-C00283
 		(R)-N-(5- cyano-5- azaspiro[2.4] heptan-7-yl)-5- (2- phenoxyphe- nyl)-1H- pyrazole-3- carboxamide 400 1HNMR (DMSO-d6, 400 MHz) δ (ppm): 13.6 (br s, 1H), 8.41-8.38 (m, 1H), 7.92-7.85(m, 1H), 7.41-7.29 (m, 4H), 7.15-7.12 (m, 1H), 7.02-6.91 (m, 4H), 4.25-4.20 (m, 1H), 3.82-3.78 (m, 1H), 3.68-3.65 (m, 1H), 3.48-3.40 (m, 1H), 3.26-3.24 (m, 1H), 0.80-0.59 (m, 4H).
7-a
Figure US11814386-20231114-C00284
 		N- ((1S,2S,4R)- 7-cyano-7- azabicyclo[2.2.1] heptan-2- yl)-5-(2- phenoxyphe- nyl)-1H- pyrazole-3- carboxamide 400 1HNMR (DMSO-d6, 400 MHz) δ (ppm): 13.7-13.6 (m, 1H), 8.62-8.51 (m, 1H), 8.05-7.87 (m, 1H) 7.45-7.25 (m, 4H), 7.19-7.12 (m, 1H), 7.04-6.95 (m, 4H), 4.27-4.13 (m, 3H), 2.22-2.08 (m, 1H), 1.83-1.65 (m, 4H).
7-b
Figure US11814386-20231114-C00285
 		N- ((1R,2R,4S)- 7-cyano-7- azabicyclo[2.2.1] heptan-2- yl)-5-(2- phenoxyphe- nyl)-1H- pyrazole-3- carboxamide 400 1HNMR (DMSO-d6, 400 MHz) δ (ppm): 13.7-13.6 (m, 1H), 8.62-8.51 (m, 1H), 8.03-7.86(m, 1H), 7.47-7.25 (m, 4H), 7.15-7.10 (m, 1H), 7.01-6.95 (m, 4H), 4.30-4.15 (m, 3H), 2.22-2.10 (m, 1H), 1.88-1.62 (m, 4H).
8-a
Figure US11814386-20231114-C00286
 		N- ((1R,4R,5S)- 2-cyano-2- azabicyclo[2.1.1] hexan-5- yl)-5-(2- phenoxyphe- nyl)-1H- pyrazole-3- carboxamide 386 1HNMR (DMSO-d6, 400 MHz) δ (ppm): 13.7 (br s, 1H), 7.94-7.88 (m, 2H), 7.41-7.28 (m, 4H), 7.16-7.12 (m, 1H), 7.03-6.92 (m, 4H), 4.20-4.19 (m, 1H), 3.83-3.82 (m, 1H), 3.45-3.43 (m, 1H), 2.94-2.92 (m, 1H), 1.78-1.76 (m, 1H), 1.32-1.29 (m, 1H).
8-b
Figure US11814386-20231114-C00287
 		N- ((1S,4S,5R)- 2-cyano-2- azabicyclo[2.1.1] hexan-5- yl)-5-(2- phenoxyphe- nyl)-1H- pyrazole-3- carboxamide 386 1HNMR (DMSO-d6, 400 MHz) δ (ppm): 13.6 (br s, 1H), 7.94-7.88 (m, 2H), 7.41-7.29 (m, 4H), 7.16-7.12 (m, 1H), 7.03-6.98 (m, 4H), 4.20-4.19 (m, 1H), 3.83-3.82 (m, 1H), 3.45-3.43 (m, 1H), 2.94-2.92 (m, 1H), 1.78-1.76 (m, 1H), 1.32-1.29 (m, 1H).
9-a
Figure US11814386-20231114-C00288
 		N-[(7S)-5- cyano-2-oxa- 5- azaspiro[3.4] octan-7-yl]-5- (2- phenoxyphe- nyl)-1H- pyrazole-3- carboxamide 416 1H-NMR (CD3OD, 400 MHz) δ (ppm): 7.80-7.77 (m, 1H), 7.39-7.35 (m, 3H), 7.28-7.25 (m, 1H), 7.16-7.13 (m, 2H), 7.03-6.97 (m, 3H), 4.97-4.93 (m, 2H), 4.74-4.70 (m, 2H), 4.55-4.50 (m, 1H), 3.86-3.81 (m, 1H), 3.54-3.50 (m, 1H), 2.68-2.63 (m, 1H), 2.53-2.48 (m, 1H).
9-b
Figure US11814386-20231114-C00289
 		N-[(7R)-5- cyano-2-oxa- 5- azaspiro[3.4] octan-7-yl]-5- (2- phenoxyphe- nyl)-1H- pyrazole-3- carboxamide 416 1H-NMR (CD30D, 400 MHz) δ (ppm): 7.80-7.77 (m, 1H), 7.39-7.35 (m, 3H), 7.28-7.25 (m, 1H), 7.16-7.13 (m, 2H), 7.03-6.97 (m, 3H), 4.97-4.90 (m, 2H), 4.74-4.70 (m, 2H), 4.55-4.51 (m, 1H), 3.86-3.82 (m, 1H), 3.54-3.50 (m, 1H), 2.68-2.63 (m, 1H), 2.53-2.48 (m, 1H).
13-a
Figure US11814386-20231114-C00290
 		N- ((1S,4R,5S)- 2-cyano-2- azabicyclo[3.1.0] hexan-4- yl)-3-(2- phenoxyphe- nyl)-1H- pyrazole-5- carboxamide 386 1H-NMR (DMSO-d6, 400 MHz) δ (ppm): 1H-NMR (DMSO-d6, 400 MHz) δ (ppm): 13.75-13.61 (m, 1H), 8.55-8.20 (m, 1H), 8.05-7.87 (m, 1H), 7.45-7.30 (m, 4H), 7.16-7.14 (m, 1H), 7.03-6.97 (m, 3H), 6.95-6.85 (m, 1H), 4.80-4.77 (m, 1H), 3.72-3.67 (m, 1H), 3.51-3.49 (m, 1H), 3.12-3.08 (m, 1H), 1.90-1.80 (m, 1H), 1.40-1.20 (m, 1H), 0.75-0.60 (m, 1H).
13-b
Figure US11814386-20231114-C00291
 		N- ((1R,4S,5R)- 2-cyano-2- azabicyclo[3.1.0] hexan-4- yl)-3-(2- phenoxyphe- nyl)-1H- pyrazole-5- carboxamide
20-a
Figure US11814386-20231114-C00292
 		N-((3aR,6aS)- 2- cyanohexahy- drocyclopenta [c]pyrrol- 3a(1H)-yl)-5- (2- phenoxyphe- nyl)-1H- pyrazole-3- carboxamide 414 1H-NMR (DMSO-d6, 400 MHz) δ (ppm): 13.70-13.58 (m, 1H), 8.55-8.21 (m, 1H), 8.03-7.86 (m, 1H), 7.45-7.13 (m, 5H), 7.04-6.92 (m, 3H), 3.70-3.66 (m, 2H), 3.54- 3.49 (m, 1H), 3.16-3.14 (m, 1H), 1.78-1.74 (m, 1H), 2.93-2.81 (m, 1H), 2.09- 1.90 (m, 3H), 1.71-1.63 (m, 2H), 1.41-1.37 (m, 1H).
20-b
Figure US11814386-20231114-C00293
 		N-((3aS,6aR)- 2- cyanohexahy- drocyclopenta [c]pyrrol- 3a(1H)-yl)-5- (2- phenoxyphe- nyl)-1H- pyrazole-3- carboxamide 414 1H-NMR (DMSO-d6, 400 MHz) δ (ppm): 13.62 (br s, 1H), 8.33 (br s, 1H), 7.94- 7.93 (m, 1H), 7.42-7.30 (m, 3H), 7.28-7.26 (m, 1H), 7.16-7.14 (m, 1H), 7.12 (br s, 1H), 7.08-6.98 (m, 3H), 3.70-3.64 (m, 2H), 3.52-3.50 (m, 1H), 3.16-3.13 (m, 1H), 2.91-2.89 (m, 1H), 2.05- 1.89 (m, 3H), 1.73-1.63 (m, 2H), 1.41-1.37 (m, 1H).
Example 3: Preparation of N-((1R,5S)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-5-(2-phenoxyphenyl)-1H-pyrazole-3-carboxamide (6-a) and N-((1S,5R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-5-(2-phenoxyphenyl)-1H-pyrazole-3-carboxamide (6-b)
Figure US11814386-20231114-C00294
Compounds 6-a and 6-b were prepared by the following route:
Figure US11814386-20231114-C00295
Step 1. Methyl 5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carboxylate
2-(Trimethylsilyl)ethoxymethyl chloride (12.2 mL, 68.8 mmol) was added dropwise to a 0° C. solution of methyl 5-bromo-1H-pyrazole-3-carboxylate (5.00 g, 24.5 mmol) and potassium carbonate (18.0 g, 130 mmol) in DMF (10 mL). The resulting mixture was stirred for 14 h at 25° C. The reaction was quenched with water (20 mL) at 0° C. The resulting mixture was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (2×100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 15:1 petroleum ether/ethyl acetate) to afford methyl 5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carboxylate (6.20 g, 76%) as a yellow oil. LCMS (ES, m/z): 335, 337 [M+H]+.
Step 2. Methyl 5-(2-phenoxyphenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carboxylate
A solution of methyl 5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carboxylate (6.20 g, 18.5 mmol), (2-phenoxyphenyl)boronic acid (4.96 g, 23.2 mmol), XPhos-Pd-G3 (3.12 g, 36.9 mmol) and potassium phosphate tribasic (25.4 mg, 37.1 mmol) in dioxane (120 mL) and water (24 mL) was stirred for 15 h at 100° C. in an oil bath. The mixture was cooled to 25° C. The resulting mixture was concentrated under vacuum. The residue was diluted with water (30 mL). The resulting mixture was extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by reverse phase chromatography (Column: XBridge Shield RP18 OBD Column, 5 μm, 30×150 mm; Mobile phase, A: water (containing 0.05% ammonium hydrogen) and B: acetonitrile (5% B to 72% over 20 min); Detector: UV 220 and 254 nm) to afford methyl 5-(2-phenoxyphenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carboxylate as a yellow solid (3.20 g, 41%). LCMS (ES, m/z): 425 [M+H]+.
Step 3. 5-(2-Phenoxyphenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carboxylic acid
A solution of methyl 5-(2-phenoxyphenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carboxylate (1.40 g, 3.30 mmol) and lithium hydroxide (810 mg, 34.0 mmol) in THF (60.0 mL), water (15.0 mL), and methanol (30.0 mL) was stirred for 4 h at 50° C. The mixture was cooled to 25° C. and concentrated under vacuum. The pH value of the residue was adjusted to 3-4 with 3 N aqueous hydrochloric acid solution. The resulting mixture was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (2×100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (eluting with 2:1 petroleum ether/ethyl acetate) to afford 5-(2-phenoxyphenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carboxylic acid as an off-white solid (1.00 g, 74%). LCMS (ES, m/z): 411 [M+H]+.
Step 4. tert-Butyl 1-(5-(2-phenoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxamido)-3-azabicyclo[3.2.0]heptane-3-carboxylate
A solution of 5-(2-phenoxyphenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carboxylic acid (300 mg, 0.723 mmol), tert-butyl 1-amino-3-azabicyclo[3.2.0]heptane-3-carboxylate (154 mg, 0.723 mmol), HATU (275 mg, 0.723 mmol) and N,N-diisopropylethylamine (0.239 mL, 1.45 mmol) in DMF (2 mL) was stirred for 40 min at 25° C. The reaction was quenched with water (5 mL). The resulting mixture was extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with brine (2×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (eluting with 4:1 petroleum ether/ethyl acetate) to afford tert-butyl 1-(5-(2-phenoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxamido)-3-azabicyclo[3.2.0]heptane-3-carboxylate as an off-white solid (350 mg, 80%). LCMS (ES, m/z): 605 [M+H]+.
Step 5. N-(3-azabicyclo[3.2.0]heptan-1-yl)-5-(2-phenoxyphenyl)-1H-pyrazole-3-carboxamide 2,2,2-trifluoroacetate
A solution of tert-butyl 1-(5-(2-phenoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxamido)-3-azabicyclo[3.2.0]heptane-3-carboxylate (350 mg, 0.579 mmol) in trifluoroacetic acid (1 mL) and dichloromethane (3 mL) was stirred for 30 min at 25° C. The resulting mixture was concentrated under vacuum to afford N-(3-azabicyclo[3.2.0]heptan-1-yl)-5-(2-phenoxyphenyl)-1H-pyrazole-3-carboxamide 2,2,2-trifluoroacetate as a brown oil (360 mg, crude). LCMS (ES, m/z): 375 [M+H]+.
Step 6. N-((1R,5S)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-5-(2-phenoxyphenyl)-1H-pyrazole-3-carboxamide (6-a) and N-((1S,5R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-5-(2-phenoxyphenyl)-1H-pyrazole-3-carboxamide (6-b)
Cyanogen bromide (72.8 mg, 0.687 mmol) was added dropwise to a 0° C. solution of N-(3-azabicyclo[3.2.0]heptan-1-yl)-5-(2-phenoxyphenyl)-1H-pyrazole-3-carboxamide 2,2,2-trifluoroacetate (350 mg, 0.763 mmol) and sodium bicarbonate (785 mg, 9.25 mmol) in DMF (2 mL). The mixture was stirred for 1 h at 25° C. The solids were filtered out. The filtrate was directly purified by Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 5 μm, 30×150 mm; Mobile phase, A: water (containing 0.05% ammonium hydrogen) and B: acetonitrile (35% B to 65% over 7 min); Detector: UV 220 and 254 nm) to afford N-(3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-5-(2-phenoxyphenyl)-1H-pyrazole-3-carboxamide as a white solid (70.0 mg). This material was separated by chiral-HPLC (Column: Chiralpak IG, 2*25 cm, 5 m; Mobile Phase, A: MTBE and B: EtOH (hold 15% in 24 min); Flow rate: 20 mL/min; Detector: 220/254 nm). The first eluting isomer was collected, and the absolute stereochemistry was arbitrarily assigned as (1R,5S): N-((1R,5S)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-5-(2-phenoxyphenyl)-1H-pyrazole-3-carboxamide (RT1=10.9 min) as a white solid (6-a, 28.5 mg, 10%). LCMS (ES, m/z): 400 [M+H]+. 1H-NMR (DMSO-d6, 400 MHz) δ (ppm): 13.68-13.62 (m, 1H), 8.92-8.61 (m, 1H), 8.03-7.86 (m, 1H), 7.42-7.23 (m, 4H), 7.21-7.12 (m, 1H), 7.03-6.89 (m, 4H), 3.73-3.70 (m, 1H), 3.68-3.56 (m, 1H), 3.39-3.31 (m, 2H), 3.08-3.05 (m, 1H), 2.34-2.31 (m, 1H), 2.20-2.08 (m, 2H), 1.61-1.58 (m, 1H). The second eluting isomer was collected, and the absolute stereochemistry was arbitrarily assigned as (1S,5R): N-((1S,5R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-5-(2-phenoxyphenyl)-1H-pyrazole-3-carboxamide (RT2=12.7 min) as a white solid (6-b, 20.6 mg, 8%). LCMS (ES, m/z): 400 [M+H]+. 1H-NMR (DMSO-d6, 400 MHz) δ (ppm): 13.68-13.62 (m, 1H), 8.92-8.61 (m, 1H), 8.03-7.86 (m, 1H), 7.42-7.29 (m, 4H), 7.21-7.12 (m, 1H), 7.04-6.89 (m, 4H), 3.73-3.70 (m, 1H), 3.68-3.54 (m, 1H), 3.39-3.31 (m, 2H), 3.08-3.05 (m, 1H), 2.34-2.31 (m, 1H), 2.20-2.08 (m, 2H), 1.61-1.58 (m, 1H). Alternatively, the absolute stereochemistry of the first and second eluting isomers could have been arbitrarily assigned as (1S,5R) and (1R,5S), respectively.
Example 4: Preparation of N-((1S,5R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-5-(2-phenoxyphenyl)-1H-pyrazole-3-carboxamide (3-a) and N-((1R,5S)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-5-(2-phenoxyphenyl)-1H-pyrazole-3-carboxamide (3-b)
Figure US11814386-20231114-C00296
Compounds 3-a and 3-b were prepared by the following route:
Figure US11814386-20231114-C00297
Step 1. Methyl 5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carboxylate
2-(Trimethylsilyl)ethoxymethyl chloride (12.2 mL, 68.8 mmol) was added dropwise to a 0° C. solution of methyl 5-bromo-1H-pyrazole-3-carboxylate (5.00 g, 24.5 mmol) and potassium carbonate (18.0 g, 130 mmol) in DMF (10 mL). The resulting mixture stirred for 14 h at 25° C. The reaction was quenched with water (20 mL) at 0° C. The resulting mixture was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (2×100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 15:1 petroleum ether/ethyl acetate) to afford methyl 5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carboxylate (6.20 g, 76%) as a yellow oil. LCMS (ES, m/z): 335, 337 [M+H]+.
Step 2. Methyl 5-(2-phenoxyphenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carboxylate
A solution of methyl 5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carboxylate (6.20 g, 18.5 mmol), (2-phenoxyphenyl)boronic acid (4.96 g, 23.2 mmol), XPhos-Pd-G3 (3.12 g, 36.9 mmol) and potassium phosphate tribasic (25.4 mg, 37.1 mmol) in dioxane (120 mL) and water (24 mL) was stirred for 15 h at 100° C. in an oil bath. The mixture was cooled to 25° C. The resulting mixture was concentrated under vacuum. The residue was diluted with water (30 mL). The resulting mixture was extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by reverse phase chromatography (Column: XBridge Shield RP18 OBD Column, 5 μm, 30×150 mm; Mobile phase, A: water (containing 0.05% ammonium hydrogen) and B: acetonitrile (5% B to 72% over 20 min); Detector: UV 220 and 254 nm) to afford methyl 5-(2-phenoxyphenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carboxylate as a yellow solid (3.20 g, 41%). LCMS (ES, m/z): 425 [M+H]+.
Step 3. 5-(2-Phenoxyphenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carboxylic acid
A solution of methyl 5-(2-phenoxyphenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carboxylate (1.40 g, 3.30 mmol) and lithium hydroxide (810 mg, 34.0 mmol) in THF (60.0 mL), water (15.0 mL), and methanol (30.0 mL) was stirred for 4 h at 50° C. The mixture was cooled to 25° C. and concentrated under vacuum. The pH value of the residue was adjusted to 3-4 with 3 N aqueous hydrochloric acid solution. The resulting mixture was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (2×100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (eluting with 2:1 petroleum ether/ethyl acetate) to afford 5-(2-phenoxyphenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carboxylic acid as an off-white solid (1.00 g, 74%). LCMS (ES, m/z): 411 [M+H]+.
Step 4. tert-butyl-(5-(2-phenoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxamido)-3-azabicyclo[3.1.0]hexane-3-carboxylate
A solution of 5-(2-phenoxyphenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carboxylic acid (300 mg, 0.723 mmol), tert-butyl 1-amino-3-azabicyclo[3.1.0]hexane-3-carboxylate (145 mg, 0.723 mmol), HATU (278 mg, 0.723 mmol) and N,N-diisopropylethylamine (0.242 mL, 1.47 mmol) in DMF (3 mL) was stirred for 30 min at 25° C. The reaction was quenched with water (10 mL) at 25° C. The resulting mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (2×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (eluting with 4:1 petroleum ether/ethyl acetate) to afford tert-butyl 1-(5-(2-phenoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxamido)-3-azabicyclo[3.1.0]hexane-3-carboxylate as an off-white solid (280 mg, 67%). LCMS (ES, m/z): 591 [M+H]+.
Step 5. N-(3-azabicyclo[3.1.0]hexan-1-yl)-5-(2-phenoxyphenyl)-1H-pyrazole-3-carboxamide 2,2,2-trifluoroacetate
A solution of tert-butyl 1-(5-(2-phenoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxamido)-3-azabicyclo[3.1.0]hexane-3-carboxylate (280 mg, 0.475 mmol) in trifluoroacetic acid (1 mL) and dichloromethane (3 mL) was stirred for 2 h at 25° C. The resulting mixture was concentrated under vacuum to afford N-(3-azabicyclo[3.1.0]hexan-1-yl)-5-(2-phenoxyphenyl)-1H-pyrazole-3-carboxamide 2,2,2-trifluoroacetate as a yellow oil (285 mg, crude). LCMS (ES, m/z): 361 [M+H]+.
Step 6. N-((1S,5R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-5-(2-phenoxyphenyl)-1H-pyrazole-3-carboxamide (3-a) and N-((1R,5S)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-5-(2-phenoxyphenyl)-1H-pyrazole-3-carboxamide (3-b)
Cyanogen bromide (58.5 mg, 0.552 mmol) was added dropwise to a 0° C. solution of N-(3-azabicyclo[3.1.0]hexan-1-yl)-5-(2-phenoxyphenyl)-1H-pyrazole-3-carboxamide 2,2,2-trifluoroacetate (280 mg, 0.613 mmol) and sodium bicarbonate (653 mg, 7.69 mmol) in DMF (2 mL). The mixture was stirred for 1 h at 25° C. The reaction was cooled to 0° C. and quenched with water (10 mL). The resulting mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 5 μm, 30×150 mm; Mobile phase, A: water (containing 0.05% ammonium hydrogen) and B: acetonitrile (28% B to 48% over 7 min); Detector: UV 220 and 254 nm) to afford N-(3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-5-(2-phenoxyphenyl)-1H-pyrazole-3-carboxamide as a white solid (60.0 mg). This material was separated by chiral-HPLC (Column: Chiralpak IG, 2*25 cm, 5 μm; Mobile Phase, A: MTBE and B: EtOH (hold 30% in 10.5 min); Flow rate: 13 mL/min; Detector: 220/254 nm). The first eluting isomer was collected, and the absolute stereochemistry was arbitrarily assigned as (1S,5R): N-((1S,5R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-5-(2-phenoxyphenyl)-1H-pyrazole-3-carboxamide (RT1=6.45 min) as a pink solid (3-a, 30.3 mg, 14%). LCMS (ES, m/z): 386 [M+H]+. 1H-NMR (DMSO-d6, 400 MHz) δ (ppm): 13.72-13.64 (m, 1H), 9.08-8.70 (m, 1H), 8.05-7.85 (m, 1H), 7.44-7.29 (m, 4H), 7.20-7.12 (m, 1H), 7.04-6.87 (m, 4H), 3.69-3.66 (m, 1H), 3.57-3.48 (m, 3H), 1.78-1.74 (m, 1H), 1.17-1.14 (m, 1H), 0.87-0.82 (m, 1H). The second eluting isomer was collected, and the absolute stereochemistry was arbitrarily assigned as (1R,5S); N-((1R,5S)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-5-(2-phenoxyphenyl)-1H-pyrazole-3-carboxamide (RT2=8.97 min) (3-b, 29.9 mg, 14%) as a white solid. LCMS (ES, m/z): 386 [M+H]+. 1H-NMR (DMSO-d6, 400 MHz) δ (ppm): 13.72-13.64 (m, 1H), 9.08-8.70 (m, 1H), 8.05-7.85 (m, 1H), 7.44-7.29 (m, 4H), 7.22-7.12 (m, 1H), 7.04-6.87 (m, 4H), 3.69-3.66 (m, 1H), 3.57-3.51 (m, 3H), 1.78-1.74 (m, 1H), 1.17-1.14 (m, 1H), 0.87-0.82 (m, 1H). Alternatively, the absolute stereochemistry of the first and second eluting isomers could have been arbitrarily assigned as (1R,5S) and (1S,5R), respectively.
Many modifications and variations of the embodiments described herein may be made without departing from the scope, as is apparent to those skilled in the art. The specific embodiments described herein are offered by way of example only.

Claims (20)

What is claimed is:
1. A method of inhibiting USP30 in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula I:
Figure US11814386-20231114-C00298
or a pharmaceutically acceptable salt thereof, wherein:
Ra, Rb, Rc, Rd, Re, Rf, Rg, and Rh are defined as follows:
(i) Ra and Rb form a C1-C4 alkylene group between the atoms to which they are attached, wherein said C1-C4 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Rc, Rd, Re, Rf, Rg, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
(ii) Ra and Re form a C1-C2 alkylene group between the atoms to which they are attached, wherein said C1-C2 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Rb, Rc, Rd, Rf, Rg, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
(iii) Ra and Rg form a C1-C3 alkylene group between the atoms to which they are attached, wherein said C1-C3 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Rb, Rc, Rd, Re, Rf, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
(iv) Rb and Re form a C1-C4 alkylene group between the atoms to which they are attached, wherein said C1-C4 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Ra, Rd, Re, Rf, Rg, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
(v) Rb and Re form a C1-C3 alkylene group between the atoms to which they are attached, wherein said C1-C3 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Ra, Rc, Rd, Rf, Rg, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
(vi) Rb and Rg form a C1-C4 alkylene group between the atoms to which they are attached, wherein said C1-C4 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Ra, Re, Rd, Re, Rf, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
(vii) Re and Rd, together with the atom to which they are attached, form a 3-6 membered cycloalkyl or heterocycloalkyl, wherein said 3-6 membered cycloalkyl or heterocycloalkyl is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Ra, Rb, Re, Rf, Rg, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
(viii) Re and Rd together form ═O; and Ra, Rb, Re, Rf, Rg, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
(ix) Rc and Re form a C1-C4 alkylene group between the atoms to which they are attached, wherein said C1-C4 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Ra, Rb, Rd, Rf, Rg, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
(x) Rc and Rg form a C1-C3 alkylene group between the atoms to which they are attached, wherein said C1-C3 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Ra, Rb, Rd, Re, Rf, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
(xi) Re and Rf, together with the atom to which they are attached, form a 3-6 membered cycloalkyl or heterocycloalkyl, wherein said 3-6 membered cycloalkyl or heterocycloalkyl is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Ra, Rb, Rc, Rd, Rg, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
(xii) Re and Rf together form ═O; and Ra, Rb, Rc, Rd, Rg, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
(xiii) Re and Rg form a C1-C3 alkylene group between the atoms to which they are attached, wherein said C1-C3 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Ra, Rb, Re, Rd, Rf, and Rh are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
(xiv) Rg and Rh, together with the atom to which they are attached, form a 3-6 membered cycloalkyl or heterocycloalkyl, wherein said 3-6 membered cycloalkyl or heterocycloalkyl is substituted with 0-4 substituents selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl; and Ra, Rb, Re, Rd, Re, and Rf are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; or
(xv) Rg and Rh together form ═O; and Ra, Rb, Rc, Rd, Re, and Rf are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; and
Ar1 is phenylene or 5-6 membered heteroarylene, wherein said phenylene or heteroarylene is substituted with m R1 groups; and
Ar2 is phenylene or 5-6 membered heteroarylene, wherein said phenylene or heteroarylene is substituted with n R2 groups;
L is —O—, —S—, —NR3—, —C(R4)2—, —S(O)2—, or —S(O)—;
M is 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein said cycloalkyl, phenyl, or heteroaryl is substituted with p R5 groups;
each occurrence of R1, R2, and R5 is independently halo, cyano, NO2, oxo, hydroxyl, —R6, —OR6, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, —C1-C6 alkylene-R6, C1-C6 alkoxy, C1-C6 haloalkoxy, —C0-C3 alkylene-NR6R7, —C0-C3 alkylene-NR7R8, —C0-C3 alkylene-C(O)NR6R7, —C0-C3 alkylene-C(O)NR7R8, —C0-C3 alkylene-NR7C(O)R6, —C0-C3 alkylene-NR7C(O)R8, —C0-C3 alkylene-NR7S(O)2R6, —C0-C3 alkylene-C(O)R6, —C0-C3 alkylene-C(O)R7, —C0-C3 alkylene-SR6, —C0-C3 alkylene-S(O)R6, —C0-C3 alkylene-S(O)2R6, —C0-C3 alkylene-S(O)2R7, —C0-C3 alkylene-S(O)2NR6R7, —C0-C3 alkylene-S(O)2NR7R8, —C0-C3 alkylene-NR7C(O)NR8R9, —C0-C3 alkylene-NR7S(O)2NR8R9, —C0-C3 alkylene-C(O)OR7, —C0-C3 alkylene-C(O)OR6, —C0-C3 alkylene-OC(O)R7, —C0-C3 alkylene-OC(O)R6, —C0-C3 alkylene-NR7C(O)OR8, or —C0-C3 alkylene-NR7S(O)2R8;
R3 is H, C1-C6 alkyl, or C1-C6 haloalkyl;
each R4 is independently H, C1-C6 alkyl, or C1-C6 haloalkyl, or two R4 groups together with the carbon atom to which they are attached form a 3-6 membered cycloalkyl or heterocycloalkyl;
each R6 is 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl, or 3-8 membered cycloalkyl, wherein said heteroaryl, heterocycloalkyl, aryl, or cycloalkyl is optionally substituted with 1-5 substituents independently selected from the group consisting of halo, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl, 3-8 membered cycloalkyl, —NR10C(O)NR11R12, —NR10R11, —C(O)R10, —NR10C(O)R11, —NR10C(O)OR11, —S(O)2R10, —C(O)NR11R11, —C(O)OR10, —S(O)2NR10R11, —NR10S(O)2R11, —OR10, —OC(O)R10, —OS(O)2R10, —OC(O)NR10R11, —OC(O)OR10, —OS(O)2NR10R11, —C(O)NR10C(O)NR11R12, —C(O)C(O)R10, —C(O)NR10C(O)R11, —C(O)NR10C(O)OR11, —C(O)S(O)2R10, —C(O)C(O)NR10R11, —C(O)C(O)OR10, —C(O)S(O)2NR10R11, —C(O)NR10S(O)2R11, —C1-C6 alkylene-R10, —C1-C6 alkylene-NR10C(O)NR11R12, —C1-C6 alkylene-NR10R11, —C1-C6 alkylene-C(O)R10, —C1-C6 alkylene-NR10C(O)R11, —C1-C6 alkylene-NR1ºC(O)OR11, —C1-C6 alkylene-S(O)2R10, —C1-C6 alkylene-C(O)NR10R11, —C1-C6 alkylene-C(O)OR10, —C1-C6 alkylene-S(O)2NR10R11, —C1-C6 alkylene-NR10S(O)2R11, —C1-C6 alkenylene-R10, —C1-C6 alkenylene-NR10C(O)NR11R12, —C1-C6 alkenylene-NR10R11, —C1-C6 alkenylene-C(O)R10, —C1-C6 alkenylene-NR10C(O)R11, —C1-C6 alkenylene-NR1ºC(O)OR11, —C1-C6 alkenylene-S(O)2R10, —C1-C6 alkenylene-C(O)NR10R11, —C1-C6 alkenylene-C(O)OR10, —C1-C6 alkenylene-S(O)2NR10R11, and —C1-C6 alkenylene-NR10S(O)2R11;
each R7, R8, and R9 is independently hydrogen or C1-C6 alkyl;
each R10, R11, and R12 is independently hydrogen, C1-C6 alkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl, or 3-8 membered cycloalkyl;
m is 0-4;
n is 0-4; and
p is 0-4.
2. The method of claim 1, wherein the compound is of formula (I-C):
Figure US11814386-20231114-C00299
or a pharmaceutically acceptable salt thereof.
3. The method of claim 2, wherein Rb and Rc form a C1-C4 alkylene group between the atoms to which they are attached, and Ra, Rd, Re, Rf, Rg, and Rh are each hydrogen.
4. The method of claim 1, wherein the compound is of formula (I-1):
Figure US11814386-20231114-C00300
or a pharmaceutically acceptable salt thereof, wherein Rj, Rk, Rm, and Rn are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl.
5. The method of claim 4, wherein the compound is of formula (I-2):
Figure US11814386-20231114-C00301
or a pharmaceutically acceptable salt thereof, wherein Rj and Rk are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl.
6. The method of claim 1, wherein the compound is of formula (I-3):
Figure US11814386-20231114-C00302
or a pharmaceutically acceptable salt thereof, wherein Rj, Rk, Rm, Rn, Ro, and Rp are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl.
7. The method of claim 1, wherein Rc and Re form a C1-C4 alkylene group between the atoms to which they are attached; and Ra, Rb, Rd, Rf, Rg, and Rh are each hydrogen.
8. The method of claim 1, wherein the compound is of formula (I-4):
Figure US11814386-20231114-C00303
or a pharmaceutically acceptable salt thereof, wherein Rq and Rr are each independently hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl.
9. The method of claim 8, wherein Ra and Re form a C1-C2 alkylene group between the atoms to which they are attached; and Rb, Rc, Rd, Rf, Rg, and Rh are each hydrogen.
10. The method of claim 1, wherein Rc and Rd, together with the atom to which they are attached, form a 3-6 membered cycloalkyl or heterocycloalkyl; and Ra, Rb, Re, Rf, Rg, and Rh are each hydrogen.
11. The method of claim 1, wherein Rc and Rg form a C1-C3 alkylene group between the atoms to which they are attached; and Ra, Rb, Rd, Re, Rf, and Rh are each hydrogen.
12. The method of claim 1, wherein Re and Rf, together with the atom to which they are attached, form a 3-6 membered cycloalkyl or heterocycloalkyl; and Ra, Rb, Rc, Rd, Rg, and Rh are each hydrogen.
13. The method of claim 1, wherein Re and Rg form a C1-C3 alkylene group between the atoms to which they are attached; and Ra, Rb, Rc, Rd, Rf, and Rh are each hydrogen.
14. The method of claim 1, wherein Ar1 is 5-6 membered heteroarylene.
15. The method of claim 14, wherein Ar2 is phenylene.
16. The method of claim 15, wherein L is —O—.
17. The method of claim 16, wherein M is phenyl substituted with p R5 groups.
18. The method of claim 17, wherein each occurrence of R1, R2, and R5 is independently halo, cyano, hydroxyl, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 hydroxyalkyl.
19. The method of claim 1, wherein each occurrence of R1, R2, and R5 is independently halo, cyano, hydroxyl, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 hydroxyalkyl.
20. A method of inhibiting USP30 in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound selected from:
Compound Number Compound Structure and Chemical Name  1-a
Figure US11814386-20231114-C00304
   (1S,5R)-2-(5-(2-phenoxyphenyl)-1H-pyrazole-3-carbonyl)-2,6- diazabicyclo[3.2.1]octane-6-carbonitrile  1-b
Figure US11814386-20231114-C00305
 (1R,5S)-2-(5-(2-phenoxyphenyl)-1H-pyrazole-3-carbonyl)-2,6- diazabicyclo[3.2.1]octane-6-carbonitrile  2-a
Figure US11814386-20231114-C00306
 N-((1S,4S,7S)-2-cyano-2-azabicyclo[2.2.1]heptan-7-yl)-5-(2-phenoxyphenyl)- 1H-pyrazole-3-carboxamide  2-b
Figure US11814386-20231114-C00307
 N-((1R,4R,7R)-2-cyano-2-azabicyclo[2.2.1]heptan-7-yl)-5-(2-phenoxyphenyl)- 1H-pyrazole-3-carboxamide  3-a
Figure US11814386-20231114-C00308
 N-((1S, 5R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-5-(2-phenoxyphenyl)-1H- pyrazole-3-carboxamide  3-b
Figure US11814386-20231114-C00309
   N-((1R, 5S)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-5-(2-phenoxyphenyl)-1H- pyrazole-3-carboxamide  4-a
Figure US11814386-20231114-C00310
   (1S,4S)-5-(5-(2-phenoxyphenyl)-1H-pyrazole-3-carbonyl)-2,5- diazabicyclo[2.2.1]heptane-2-carbonitrile  4-b
Figure US11814386-20231114-C00311
   (1R,4R)-5-(5-(2-phenoxyphenyl)-1H-pyrazole-3-carbonyl)-2,5- diazabicyclo[2.2.1]heptane-2-carbonitrile  5-a
Figure US11814386-20231114-C00312
   (S)-N-(5-cyano-5-azaspiro[2.4]heptan-7-yl)-5-(2-phenoxyphenyl)-1H- pyrazole-3-carboxamide  5-b
Figure US11814386-20231114-C00313
   (R)-N-(5-cyano-5-azaspiro[2.4]heptan-7-yl)-5-(2-phenoxyphenyl)-1H- pyrazole-3-carboxamide  6-a
Figure US11814386-20231114-C00314
   N-((1R,5S)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-5-(2-phenoxyphenyl)-1H- pyrazole-3-carboxamide  6-b
Figure US11814386-20231114-C00315
   N-((1S,5R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-5-(2-phenoxyphenyl)-1H- pyrazole-3-carboxamide  7-a
Figure US11814386-20231114-C00316
   N-((1S,2S,4R)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-5-(2-phenoxyphenyl)- 1H-pyrazole-3-carboxamide  7-b
Figure US11814386-20231114-C00317
   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-5-(2-phenoxyphenyl)- 1H-pyrazole-3-carboxamide  8-a
Figure US11814386-20231114-C00318
   N-[(1R,4R,5S)-2-cyano-2-azabicyclo[2.1.1]hexan-5-yl]-5-(2-phenoxyphenyl)- 1H-pyrazole-3-carboxamide  8-b
Figure US11814386-20231114-C00319
   N-((1S,4S,5R)-2-cyano-2-azabicyclo[2.1.1]hexan-5-yl)-5-(2-phenoxyphenyl)- 1H-pyrazole-3-carboxamide  9-a
Figure US11814386-20231114-C00320
   (S)-N-(5-cyano-2-oxa-5-azaspiro[3.4]octan-7-yl)-5-(2-phenoxyphenyl)-1H- pyrazole-3-carboxamide  9-b
Figure US11814386-20231114-C00321
   (R)-N-(5-cyano-2-oxa-5-azaspiro[3.4]octan-7-yl)-5-(2-phenoxyphenyl)-1H- arazole-3-carboxamide 13-a
Figure US11814386-20231114-C00322
   N-((1S,4R,5S)-2-cyano-2-azabicyclo[3.1.0]hexan-4-yl)-3-(2-phenoxyphenyl)- 1H-pyrazole-5-carboxamide 13-b
Figure US11814386-20231114-C00323
   N-((1R,4S,5R)-2-cyano-2-azabicyclo[3.1.0]hexan-4-yl)-3-(2-phenoxyphenyl)- 1H-pyrazole-5-carboxamide 20-a
Figure US11814386-20231114-C00324
   N-((3aR,6aS)-2-cyanohexahydrocyclopenta[c]pyrrol-3a(1H)-yl)-5-(2- phenoxyphenyl)-1H-pyrazole-3-carboxamide 20-b
Figure US11814386-20231114-C00325
   N-((3aS,6aR)-2-cyanohexahydrocyclopenta[c]pyrrol-3a(1H)-yl)-5-(2- phenoxyphenyl)-1H-pyrazole-3-carboxamide 10
Figure US11814386-20231114-C00326
   (S)-N-(1-cyano-4-oxopyrrolidin-3-yl)-5-(2-phenoxyphenyl)-1H-pyrazole-3- carboxamide 11
Figure US11814386-20231114-C00327
   N-(1-cyano-2-oxopyrrolidin-3-yl)-5-(2-phenoxyphenyl)-1H-pyrazole-3- carboxamide 12
Figure US11814386-20231114-C00328
   N-((1S,4S,5S)-2-cyano-2-azabicyclo[3.1.0]hexan-4-yl)-3-(2-phenoxyphenyl)- 1H-pyrazole-5-carboxamide 13
Figure US11814386-20231114-C00329
   N-((1R,4S,5R)-2-cyano-2-azabicyclo[3.1.0]hexan-4-yl)-3-(2-phenoxyphenyl)- 1H-pyrazole-5-carboxamide 14
Figure US11814386-20231114-C00330
   N-((1S,4R,5S)-2-cyano-2-azabicyclo[3.1.0]hexan-4-yl)-3-(2-phenoxyphenyl)- 1H-pyrazole-5-carboxamide 15
Figure US11814386-20231114-C00331
   N-((1R,4R,5R)-2-cyano-2-azabicyclo[3.1.0]hexan-4-yl)-3-(2-phenoxyphenyl)- 1H-pyrazole-5-carboxamide 16
Figure US11814386-20231114-C00332
   N-((4S,8S)-6-cyano-1-oxa-6-azaspiro[3.4]octan-8-yl)-5-(2-phenoxyphenyl)- 1H-pyrazole-3-carboxamide 17
Figure US11814386-20231114-C00333
   N-((4R,8S)-6-cyano-1-oxa-6-azaspiro[3.4]octan-8-yl)-5-(2-phenoxyphenyl)- 1H-pyrazole-3-carboxamide 18
Figure US11814386-20231114-C00334
   N-((4S,8R)-6-cyano-1-oxa-6-azaspiro[3.4]octan-8-yl)-5-(2-phenoxyphenyl)- 1H-pyrazole-3-carboxamide 19
Figure US11814386-20231114-C00335
   N-((4R,8R)-6-cyano-1-oxa-6-azaspiro[3.4]octan-8-yl)-5-(2-phenoxyphenyl)- 1H-byrazole-3-carboxamide 20
Figure US11814386-20231114-C00336
   N-((3aR,6aS)-2-cyanohexahydrocyclopenta[c]pyrrol-3a(1H)-yl)-5-(2- phenoxyphenyl)-1H-pyrazole-3-carboxamide 21
Figure US11814386-20231114-C00337
   N-((3aS,6aR)-2-cyanohexahydrocyclopenta[c]pyrrol-3a(1H)-yl)-5-(2- phenoxyphenyl)-1H-pyrazole-3-carboxamide 22
Figure US11814386-20231114-C00338
   N-((1R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-5-(2-phenoxyphenyl)-1H- pyrazole-3-carboxamide 23
Figure US11814386-20231114-C00339
   N-((1R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-5-(2-(4- fluorophenoxy)phenyl)-1H-pyrazole-3-carboxamide 24
Figure US11814386-20231114-C00340
   N-((1R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-5-(2-(phenylthio)phenyl)- 1H-pyrazole-3-carboxamide 25
Figure US11814386-20231114-C00341
   N-((1R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-5-(2-((4- fluorophenyl)thio)phenyl)-1H-pyrazole-3-carboxamide 26
Figure US11814386-20231114-C00342
   N-((1R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-5-(2-(phenylamino)phenyl)- 1H-pyrazole-3-carboxamide 27
Figure US11814386-20231114-C00343
   N-((1R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-5-(2-((4- fluorophenyl)amino)phenyl)-1H-pyrazole-3-carboxamide 28
Figure US11814386-20231114-C00344
   N-((1R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-5-(4-phenoxypyridin-3-yl)- 1H-pyrazole-3-carboxamide 29
Figure US11814386-20231114-C00345
   N-((1R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-5-(4-(4- fluorophenoxy)pyridin-3-yl)-1H-pyrazole-3-carboxamide 30
Figure US11814386-20231114-C00346
   N-((1R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-5-(4-(phenylthio)pyridin-3- yl)-1H-pyrazole-3-carboxamide 31
Figure US11814386-20231114-C00347
   N-((1R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-5-(4-((4- fluorophenyl)thio)pyridin-3-yl)-1H-pyrazole-3-carboxamide 32
Figure US11814386-20231114-C00348
   N-((1R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-5-(4-(phenylamino)pyridin- 3-yl)-1H-pyrazole-3-carboxamide 33
Figure US11814386-20231114-C00349
   N-((1R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-5-(4-((4- fluorophenyl)amino)pyridin-3-yl)-1H-pyrazole-3-carboxamide 34
Figure US11814386-20231114-C00350
   N-((1R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-5-(3-phenoxypyridin-4-yl)- 1H-pyrazole-3-carboxamide 35
Figure US11814386-20231114-C00351
   N-((1R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-5-(3-(4- fluoraphenoxy)pyridin-4-yl)-1H-pyrazole-3-carboxamide 36
Figure US11814386-20231114-C00352
   N-((1R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-5-(3-(phenylthio)pyridin-4- yl)-1H-pyrazole-3-carboxamide 37
Figure US11814386-20231114-C00353
   N-((1R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-5-(3-((4- fluorophenyl)thio)pyridin-4-1)-1H-pyrazole-3-carboxamide 38
Figure US11814386-20231114-C00354
   N-((1R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-5-(3-(phenylamino)pyridin- 4-yl)-1H-pyrazole-3-carboxamide 39
Figure US11814386-20231114-C00355
   N-((1R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-5-(3-((4- fluorophenyl)amino)pyridin-4-yl)-1H-pyrazole-3-carboxamide 40
Figure US11814386-20231114-C00356
   N-((1R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-5-(2- phenoxyphenyl)thiazole-2-carboxamide 41
Figure US11814386-20231114-C00357
   N-((1R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-5-(2-(4- fluorophenoxy)phenyl)thiazole-2-carboxamide 42
Figure US11814386-20231114-C00358
   N-((1R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-5-(2- (phenylthio)phenyl)thiazole-2-carboxamide 43
Figure US11814386-20231114-C00359
   N-((1R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-5-(2-((4- fluorophenyl)thio)phenyl)thiazole-2-carboxamide 44
Figure US11814386-20231114-C00360
   N-((1R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-5-(2- (phenylamino)phenyl)thiazole-2-carboxamide 45
Figure US11814386-20231114-C00361
   N-((1R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-5-(2-((4- fluorophenyl)amino)phenyl)thiazole-2-carboxamide 46
Figure US11814386-20231114-C00362
   N-((1R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-5-(4-phenoxypyridin-3- yl)thiazole-2-carboxamide 47
Figure US11814386-20231114-C00363
   N-((1R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-5-(4-(4- fluorophenoxy)pyridin-3-yl)thiazole-2-carboxamide 48
Figure US11814386-20231114-C00364
   N-((1R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-5-(4-(phenylthio)pyridin-3- yl)thiazole-2-carboxamide 49
Figure US11814386-20231114-C00365
   N-((1R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-5-(4-((4- fluorophenyl)thio)pyridin-3-yl)thiazole-2-carboxamide 50
Figure US11814386-20231114-C00366
 N-((1R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-5-(4-(phenylamino)pyridin- 3-yl)thiazole-2-carboxamide 51
Figure US11814386-20231114-C00367
 N-((1R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-5-(4-((4- fluorophenyl)amino)pyridin-3-yl)thiazole-2-carboxamide 52
Figure US11814386-20231114-C00368
 N-((1R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-5-(3-phenoxypyridin-4- yl)thiazole-2-carboxamide 53
Figure US11814386-20231114-C00369
 N-((1R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-5-(3-(4- fluorophenoxy)pyridin-4-yl)thiazole-2-carboxamide 54
Figure US11814386-20231114-C00370
 N-((1R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-5-(3-(phenylthio)pyridin-4- yl)thiazole-2-carboxamide 55
Figure US11814386-20231114-C00371
 N-((1R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-5-(3-((4- fluorophenyl)thio)pyridin-4-yl)thiazole-2-carboxamide 56
Figure US11814386-20231114-C00372
 N-((1R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-5-(3-(phenylamino)pyridin- 4-yl)thiazole-2-carboxamide 57
Figure US11814386-20231114-C00373
 N-((1R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-5-(3-((4- fluorophenyl)amino)pyridin-4-yl)thiazole-2-carboxamide 58
Figure US11814386-20231114-C00374
 N-((1R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-2′-phenoxy-[1,1′-biphenyl]- 4-carboxamide 59
Figure US11814386-20231114-C00375
 N-((1R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-2′-(4-fluorophenoxy)-[1,1′- biphenyl]-4-carboxamide 60
Figure US11814386-20231114-C00376
 N-((1R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-2′-(phenylthio)-[1,1′- biphenyl]-4-carboxamide 61
Figure US11814386-20231114-C00377
 N-((1R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-2′-((4-fluorophenyl)thio)- [1,1′-biphenyl]-4-carboxamide 62
Figure US11814386-20231114-C00378
 N-((1R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-2′-(phenylamino)-[1,1′- biphenyl]-4-carboxamide 63
Figure US11814386-20231114-C00379
 N-((1R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-2′-((4-fluorophenyl)amino)- [1,1′-biphenyl]-4-carboxamide 64
Figure US11814386-20231114-C00380
 N-((1R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-4-(4-phenoxypyridin-3- yl)benzamide 65
Figure US11814386-20231114-C00381
 N-((1R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-4-(4-(4- fluorophenoxy)pyridin-3-yl)benzamide 66
Figure US11814386-20231114-C00382
 N-((1R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-4-(4-(phenylthio)pyridin-3- yl)benzamide 67
Figure US11814386-20231114-C00383
 N-((1R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-4-(4-((4- fluorophenyl)thio)pyridin-3-yl)benzamide 68
Figure US11814386-20231114-C00384
 N-((1R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-4-(4-(phenylamino)pyridin- 3-yl)benzamide 69
Figure US11814386-20231114-C00385
 N-((1R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-4-(4-((4- fluorophenyl)amino)pyridin-3-yl)benzamide 70
Figure US11814386-20231114-C00386
 N-((1R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-4-(3-phenoxypyridin-4- yl)benzamide 71
Figure US11814386-20231114-C00387
 N-((1R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-4-(3-(4- fluorophenoxy)pyridin-4-yl)benzamide 72
Figure US11814386-20231114-C00388
 N-((1R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-4-(3-(phenylthio)pyridin-4- yl)benzamide 73
Figure US11814386-20231114-C00389
 N-((1R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-4-(3-((4- fluorophenyl)thio)pyridin-4-yl)benzamide 74
Figure US11814386-20231114-C00390
 N-((1R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-4-(3-(phenylamino)pyridin- 4-yl)benzamide 75
Figure US11814386-20231114-C00391
 N-((1R)-3-cyano-3-azabicyclo[3.2.0]heptan-1-yl)-4-(3-((4- fluorophenyl)amino)pyridin-4-yl)benzamide 76
Figure US11814386-20231114-C00392
 N-((1R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-5-(2-phenoxyphenyl)-1H- pyrazole-3-carboxamide 77
Figure US11814386-20231114-C00393
 N-((1R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-5-(2-(4- fluorophenoxy)phenyl)-1H-pyrazole-3-carboxamide 78
Figure US11814386-20231114-C00394
 N-((1R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-5-(2-(phenylthio)phenyl)-1H- arazole-3-carboxamide 79
Figure US11814386-20231114-C00395
 N-((1R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-5-(2-((4- fluorophenyl)thio)phenyl)-1H-pyrazole-3-carboxamide 80
Figure US11814386-20231114-C00396
 N-((1R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-5-(2-(phenylamino)phenyl)- 1H-pyrazole-3-carboxamide 81
Figure US11814386-20231114-C00397
 N-((1R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-5-(2-((4- fluorophenyl)amino)phenyl)-1H-pyrazole-3-carboxamide 82
Figure US11814386-20231114-C00398
 N-((1R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-5-(4-phenoxypyridin-3-yl)- 1H-pyrazole-3-carboxamide 83
Figure US11814386-20231114-C00399
 N-((1R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-5-(4-(4- fluorophenoxy)pyridin-3-yl)-1H-pyrazole-3-carboxamide 84
Figure US11814386-20231114-C00400
 N-((1R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-5-(4-(phenylthio)pyridin-3- yl)-1H-pyrazole-3-carboxamide 85
Figure US11814386-20231114-C00401
 N-((1R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-5-(4-((4- fluorophenyl)thio)pyridin-3-1)-1H-pyrazole-3-carboxamide 86
Figure US11814386-20231114-C00402
 N-((1R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-5-(4-(phenylamino)pyridin-3- yl)-1H-pyrazole-3-carboxamide 87
Figure US11814386-20231114-C00403
 N-((1R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-5-(4-((4- fluorophenyl)amino)pyridin-3-yl)-1H-pyrazole-3-carboxamide 88
Figure US11814386-20231114-C00404
 N-((1R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-5-(3-phenoxypyridin-4-yl)- 1H-pyrazole-3-carboxamide 89
Figure US11814386-20231114-C00405
 N-((1R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-5-(3-(4- fluorophenoxy)pyridin-4-yl)-1H-pyrazole-3-carboxamide 90
Figure US11814386-20231114-C00406
 N-((1R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-5-(3-(phenylthio)pyridin-4- yl)-1H-pyrazole-3-carboxamide 91
Figure US11814386-20231114-C00407
 N-((1R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-5-(3-((4- fluorophenyl)thio)pyridin-4-yl)-1H-pyrazole-3-carboxamide 92
Figure US11814386-20231114-C00408
 N-((1R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-5-(3-(phenylamino)pyridin-4- yl)-1H-pyrazole-3-carboxamide 93
Figure US11814386-20231114-C00409
 N-((1R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-5-(3-((4- fluorophenyl)amino)pyridin-4-yl)-1H-pyrazole-3-carboxamide 94
Figure US11814386-20231114-C00410
 N-((1R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-5-(2-phenoxyphenyl)thiazole- 2-carboxamide 95
Figure US11814386-20231114-C00411
 N-((1R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-5-(2-(4- fluorophenoxy)phenyl)thiazole-2-carboxamide 96
Figure US11814386-20231114-C00412
 N-((1R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-5-(2- (phenylthio)phenyl)thiazole-2-carboxamide 97
Figure US11814386-20231114-C00413
 N-((1R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-5-(2-((4- fluorophenyl)thio)phenyl)thiazole-2-carboxamide 98
Figure US11814386-20231114-C00414
 N-((1R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-5-(2- (phenylamino)phenyl)thiazole-2-carboxamide 99
Figure US11814386-20231114-C00415
 N-((1R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-5-(2-((4- fluorophenyl)amino)phenyl)thiazole-2-carboxamide 100
Figure US11814386-20231114-C00416
 N-((1R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-5-(4-phenoxypyridin-3- yl)thiazole-2-carboxamide 101
Figure US11814386-20231114-C00417
 N-((1R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-5-(4-(4- fluorophenoxy)pyridin-3-yl)thiazole-2-carboxamide 102
Figure US11814386-20231114-C00418
 N-((1R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-5-(4-(phenylthio)pyridin-3- yl)thiazole-2-carboxamide 103
Figure US11814386-20231114-C00419
 N-((1R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-5-(4-((4- fluorophenyl)thio)pyridin-3-yl)thiazole-2-carboxamide 104
Figure US11814386-20231114-C00420
 N-((1R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-5-(4-(phenylamino)pyridin-3- yl)thiazole-2-carboxamide 105
Figure US11814386-20231114-C00421
 N-((1R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-5-(4-((4- fluorophenyl)amino)pyridin-3-yl)thiazole-2-carboxamide 106
Figure US11814386-20231114-C00422
 N-((1R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-5-(3-phenoxypyridin-4- yl)thiazole-2-carboxamide 107
Figure US11814386-20231114-C00423
 N-((1R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-5-(3-(4- fluorophenoxy)pyridin-4-yl)thiazole-2-carboxamide 108
Figure US11814386-20231114-C00424
 N-((1R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-5-(3-(phenylthio)pyridin-4- yl)thiazole-2-carboxamide 109
Figure US11814386-20231114-C00425
 N-((1R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-5-(3-((4- fluorophenyl)thio)pyridin-4-yl)thiazole-2-carboxamide 110
Figure US11814386-20231114-C00426
 N-((1R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-5-(3-(phenylamino)pyridin-4- yl)thiazole-2-carboxamide 111
Figure US11814386-20231114-C00427
 N-((1R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-5-(3-((4- fluorophenyl)amino)pyridin-4-yl)thiazole-2-carboxamide 112
Figure US11814386-20231114-C00428
 N-((1R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-2′-phenoxy-[1,1′-biphenyl]-4- carboxamide 113
Figure US11814386-20231114-C00429
 N-((1R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-2′-(4-fluorophenoxy)-[1,1′- biphenyl]-4-carboxamide 114
Figure US11814386-20231114-C00430
 N-((1R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-2′-(phenylthio)-[1,1′- biphenyl]-4-carboxamide 115
Figure US11814386-20231114-C00431
 N-((1R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-2′-((4-fluorophenyl)thio)- [1,1′-biphenyl]-4-carboxamide 116
Figure US11814386-20231114-C00432
 N-((1R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-2′-(phenylamino)-[1,1′- biphenyl]-4-carboxamide 117
Figure US11814386-20231114-C00433
 N-((1R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-2′-(4-fluorophenyl)amino)- [1,1′-biphenyl]-4-carboxamide 118
Figure US11814386-20231114-C00434
 N-((1R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-4-(4-phenoxypyridin-3- yl)benzamide 119
Figure US11814386-20231114-C00435
 N-((1R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-4-(4-((4- fluorophenoxy)pyridin-3-yl)benzamide 120
Figure US11814386-20231114-C00436
 N-((1R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-4-(4-(phenylthio)pyridin-3- yl)benzamide 121
Figure US11814386-20231114-C00437
 N-((1R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-4-(4-((4- fluorophenyl)thio)pyridin-3-yl)benzamide 122
Figure US11814386-20231114-C00438
 N-((1R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-4-(4-(phenylamino)pyridin-3- yl)benzamide 123
Figure US11814386-20231114-C00439
 N-((1R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-4-(4-((4- fluorophenyl)amino)pyridin-3-yl)benzamide 124
Figure US11814386-20231114-C00440
 N-((1R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-4-(3-phenoxypyridin-4- yl)benzamide 125
Figure US11814386-20231114-C00441
 N-((1R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-4-(3-(4- fluorophenoxy)pyridin-4-yl)benzamide 126
Figure US11814386-20231114-C00442
 N-((1R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-4-(3-(phenylthio)pyridin-4- yl)benzamide 127
Figure US11814386-20231114-C00443
 N-((1R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-4-(3-((4- fluorophenyl)thio)pyridin-4-yl)benzamide 128
Figure US11814386-20231114-C00444
 N-((1R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-4-(3-(phenylamino)pyridin-4- yl)benzamide 129
Figure US11814386-20231114-C00445
 N-((1R)-3-cyano-3-azabicyclo[3.1.0]hexan-1-yl)-4-(3-((4- fluorophenyl)amino)pyridin-4-yl)benzamide 130
Figure US11814386-20231114-C00446
 N-((7R)-2-cyano-2-azabicyclo[2.2.1]heptan-7-yl)-5-(2-phenoxyphenyl)-1H- pyrazole-3-carboxamide 131
Figure US11814386-20231114-C00447
 N-((7R)-2-cyano-2-azabicyclo[2.2.1]heptan-7-yl)-5-(2-(4- fluorophenoxy)phenyl)-1H-pyrazole-3-carboxamide 132
Figure US11814386-20231114-C00448
 N-((7R)-2-cyano-2-azabicyclo[2.2.1]heptan-7-yl)-5-(2-(phenylthio)phenyl)- 1H-pyrazole-3-carboxamide 133
Figure US11814386-20231114-C00449
 N-((7R)-2-cyano-2-azabicyclo[2.2.1]heptan-7-yl)-5-(2-((4- fluorophenyl)thio)phenyl)-1H-pyrazole-3-carboxamide 134
Figure US11814386-20231114-C00450
 N-((7R)-2-cyano-2-azabicyclo[2.2.1]heptan-7-yl)-5-(2-(phenylamino)phenyl)- 1H-pyrazole-3-carboxamide 135
Figure US11814386-20231114-C00451
 N-((7R)-2-cyano-2-azabicyclo[2.2.1]heptan-7-yl)-5-(2-((4- fluorophenyl)amino)phenyl)-1H-pyrazole-3-carboxamide 136
Figure US11814386-20231114-C00452
 N-((7R)-2-cyano-2-azabicyclo[2.2.1]heptan-7-yl)-5-(4-phenoxypyridin-3-yl)- 1H-pyrazole-3-carboxamide 137
Figure US11814386-20231114-C00453
 N-((7R)-2-cyano-2-azabicyclo[2.2.1]heptan-7-yl)-5-(4-(4- fluorophenoxy)pyridin-3-yl)-1H-pyrazole-3-carboxamide 138
Figure US11814386-20231114-C00454
 N-((7R)-2-cyano-2-azabicyclo[2.2.1]heptan-7-yl)-5-(4-(phenylthio)pyridin-3- yl)-1H-pyrazole-3-carboxamide 139
Figure US11814386-20231114-C00455
 N-((7R)-2-cyano-2-azabicyclo[2.2.1]heptan-7-yl)-5-(4-((4- fluorophenyl)thio)pyridin-3-yl)-1H-pyrazole-3-carboxamide 140
Figure US11814386-20231114-C00456
 N-((7R)-2-cyano-2-azabicyclo[2.2.1]heptan-7-yl)-5-(4-(phenylamino)pyridin- 3-yl)-1H-pyrazole-3-carboxamide 141
Figure US11814386-20231114-C00457
 N-((7R)-2-cyano-2-azabicyclo[2.2.1]heptan-7-yl)-5-(4-((4- fluorophenyl)amino)pyridin-3-yl)-1H-pyrazole-3-carboxamide 142
Figure US11814386-20231114-C00458
 N-((7R)-2-cyano-2-azabicyclo[2.2.1]heptan-7-yl)-5-(3-phenoxypyridin-4-yl)- 1H-pyrazole-3-carboxamide 143
Figure US11814386-20231114-C00459
 N-((7R)-2-cyano-2-azabicyclo[2.2.1]heptan-7-yl)-5-(3-(4- fluorophenoxy)pyridin-4-yl)-1H-pyrazole-3-carboxamide 144
Figure US11814386-20231114-C00460
 N-((7R)-2-cyano-2-azabicyclo[2.2.1]heptan-7-yl)-5-(3-(phenylthio)pyridin-4- yl)-1H-pyrazole-3-carboxamide 145
Figure US11814386-20231114-C00461
 N-((7R)-2-cyano-2-azabicyclo[2.2.1]heptan-7-yl)-5-(3-((4- fluorophenyl)thio)pyridin-4-1)-1H-pyrazole-3-carboxamide 146
Figure US11814386-20231114-C00462
 N-((7R)-2-cyano-2-azabicyclo[2.2.1]heptan-7-yl)-5-(3-(phenylamino)pyridin- 4-yl)-1H-pyrazole-3-carboxamide 147
Figure US11814386-20231114-C00463
 N-((7R)-2-cyano-2-azabicyclo[2.2.1]heptan-7-yl)-5-(3-((4- fluoraphenyl)amino)pyridin-4-yl)-1H-pyrazole-3-carboxamide 148
Figure US11814386-20231114-C00464
 N-((7R)-2-cyano-2-azabicyclo[2.2.1]heptan-7-yl)-5-(2- phenoxyphenyl)thiazole-2-carboxamide 149
Figure US11814386-20231114-C00465
 N-((7R)-2-cyano-2-azabicyclo[2.2.1]heptan-7-yl)-5-(2-(4- fluorophenoxy)phenyl)thiazole-2-carboxamide 150
Figure US11814386-20231114-C00466
 N-((7R)-2-cyano-2-azabicyclo[2.2.1]heptan-7-yl)-5-(2- (phenylthio)phenyl)thiazole-2-carboxamide 151
Figure US11814386-20231114-C00467
 N-((7R)-2-cyano-2-azabicyclo[2.2.1]heptan-7-yl)-5-(2-((4- fluorophenyl)thio)phenyl)thiazole-2-carboxamide 152
Figure US11814386-20231114-C00468
 N-((7R)-2-cyano-2-azabicyclo[2.2.1]heptan-7-yl)-5-(2- (phenylamino)phenyl)thiazole-2-carboxamide 153
Figure US11814386-20231114-C00469
 N-((7R)-2-cyano-2-azabicyclo[2.2.1]heptan-7-yl)-5-(2-((4- fluorophenyl)amino)phenyl)thiazole-2-carboxamide 154
Figure US11814386-20231114-C00470
 N-((7R)-2-cyano-2-azabicyclo[2.2.1]heptan-7-yl)-5-(4-phenoxypyridin-3- yl)thiazole-2-carboxamide 155
Figure US11814386-20231114-C00471
 N-((7R)-2-cyano-2-azabicyclo[2.2.1]heptan-7-yl)-5-(4-(4- fluorophenoxy)pyridin-3-yl)thiazole-2-carboxamide 156
Figure US11814386-20231114-C00472
 N-((7R)-2-cyano-2-azabicyclo[2.2.1]heptan-7-yl)-5-(4-(phenylthio)pyridin-3- yl)thiazole-2-carboxamide 157
Figure US11814386-20231114-C00473
 N-((7R)-2-cyano-2-azabicyclo[2.2.1]heptan-7-yl)-5-(4-((4- fluorophenyl)thio)pyridin-3-yl)thiazole-2-carboxamide 158
Figure US11814386-20231114-C00474
 N-((7R)-2-cyano-2-azabicyclo[2.2.1]heptan-7-yl)-5-(4-(phenylamino)pyridin- 3-yl)thiazole-2-carboxamide 159
Figure US11814386-20231114-C00475
 N-((7R)-2-cyano-2-azabicyclo[2.2.1]heptan-7-yl)-5-(4-((4- fluorophenyl)amino)pyridin-3-yl)thiazole-2-carboxamide 160
Figure US11814386-20231114-C00476
 N-((7R)-2-cyano-2-azabicyclo[2.2.1]heptan-7-yl)-5-(3-phenoxypyridin-4- yl)thiazole-2-carboxamide 161
Figure US11814386-20231114-C00477
 N-((7R)-2-cyano-2-azabicyclo[2.2.1]heptan-7-yl)-5-(3-(4- fluorophenoxy)pyridin-4-yl)thiazole-2-carboxamide 162
Figure US11814386-20231114-C00478
 N-((7R)-2-cyano-2-azabicyclo[2.2.1]heptan-7-yl)-5-(3-(phenylthio)pyridin-4- yl)thiazole-2-carboxamide 163
Figure US11814386-20231114-C00479
 N-((7R)-2-cyano-2-azabicyclo[2.2.1]heptan-7-yl)-5-(3-((4- fluorophenyl)thio)pyridin-4-yl)thiazole-2-carboxamide 164
Figure US11814386-20231114-C00480
 N-((7R)-2-cyano-2-azabicyclo[2.2.1]heptan-7-yl)-5-(3-(phenylamino)pyridin- 4-yl)thiazole-2-carboxamide 165
Figure US11814386-20231114-C00481
 N-((7R)-2-cyano-2-azabicyclo[2.2.1]heptan-7-yl)-5-(3-((4- fluorophenyl)amino)pyridin-4-yl)thiazole-2-carboxamide 166
Figure US11814386-20231114-C00482
 N-((7R)-2-cyano-2-azabicyclo[2.2.1]heptan-7-yl)-2′-phenoxy-[1,1′-biphenyl]- 4-carboxamide 167
Figure US11814386-20231114-C00483
 N-((7R)-2-cyano-2-azabicyclo[2.2.1]heptan-7-yl)-2′-(4-fluorophenoxy)-[1,1′- biphenyl]-4-carboxamide 168
Figure US11814386-20231114-C00484
 N-((7R)-2-cyano-2-azabicyclo[2.2.1]heptan-7-yl)-2′-(phenylthio)-[1,1′- biphenyl]-4-carboxamide 169
Figure US11814386-20231114-C00485
 N-((7R)-2-cyano-2-azabicyclo[2.2.1]heptan-7-yl)-2′-(4-fluorophenyl)thio)- [1,1′-biphenyl]-4-carboxamide 170
Figure US11814386-20231114-C00486
 N-((7R)-2-cyano-2-azabicyclo[2.2.1]heptan-7-yl)-2′-(phenylamino)-[1,1′- biphenyl]-4-carboxamide 171
Figure US11814386-20231114-C00487
 N-((7R)-2-cyano-2-azabicyclo[2.2.1]heptan-7-yl)-2′-(4-fluorophenyl)amino)- [1,1′-biphenyl]-4-carboxamide 172
Figure US11814386-20231114-C00488
 N-((7R)-2-cyano-2-azabicyclo[2.2.1]heptan-7-yl)-4-(4-phenoxypyridin-3- yl)benzamide 173
Figure US11814386-20231114-C00489
 N-((7R)-2-cyano-2-azabicyclo[2.2.1]heptan-7-yl)-4-(4-(4- fluorophenoxy)pyridin-3-yl)benzamide 174
Figure US11814386-20231114-C00490
 N-((7R)-2-cyano-2-azabicyclo[2.2.1]heptan-7-yl)-4-(4-(phenylthio)pyridin-3- yl)benzamide 175
Figure US11814386-20231114-C00491
 N-((7R)-2-cyano-2-azabicyclo[2.2.1]heptan-7-yl)-4-(4-((4- fluorophenyl)thio)pyridin-3-yl)benzamide 176
Figure US11814386-20231114-C00492
 N-((7R)-2-cyano-2-azabicyclo[2.2.1]heptan-7-yl)-4-(4-(phenylamino)pyridin- 3-yl)benzamide 177
Figure US11814386-20231114-C00493
 N-((7R)-2-cyano-2-azabicyclo[2.2.1]heptan-7-yl)-4-(4-((4- fluorophenyl)amino)pyridin-3-yl)benzamide 178
Figure US11814386-20231114-C00494
 N-((7R)-2-cyano-2-azabicyclo[2.2.1]heptan-7-yl)-4-(3-phenoxypyridin-4- yl)benzamide 179
Figure US11814386-20231114-C00495
 N-((7R)-2-cyano-2-azabicyclo[2.2.1]heptan-7-yl)-4-(3-(4- fluorophenoxy)pyridin-4-yl)benzamide 180
Figure US11814386-20231114-C00496
 N-((7R)-2-cyano-2-azabicyclo[2.2.1]heptan-7-yl)-4-(3-(phenylthio)pyridin-4- yl)benzamide 181
Figure US11814386-20231114-C00497
 N-((7R)-2-cyano-2-azabicyclo[2.2.1]heptan-7-yl)-4-(3-((4- fluorophenyl)thio)pyridin-4-yl)benzamide 182
Figure US11814386-20231114-C00498
 N-((7R)-2-cyano-2-azabicyclo[2.2.1]heptan-7-yl)-4-(3-(phenylamino)pyridin- 4-yl)benzamide 183
Figure US11814386-20231114-C00499
 N-((7R)-2-cyano-2-azabicyclo[2.2.1]heptan-7-yl)-4-(3-((4- fluorophenyl)amino)pyridin-4-yl)benzamide.
or a pharmaceutically acceptable salt thereof.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12049466B2 (en) 2018-05-17 2024-07-30 Forma Therapeutics, Inc. Fused bicyclic compounds useful as ubiquitin-specific peptidase 30 inhibitors

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019071073A1 (en) 2017-10-06 2019-04-11 Forma Therapeutics, Inc. Inhibiting ubiquitin specific peptidase 30
BR112021003620A2 (en) 2018-10-05 2021-05-18 Forma Therapeutics, Inc. Fused pyrrolines that act as specific protease inhibitors for ubiquitin 30 (usp30)
GB201912674D0 (en) 2019-09-04 2019-10-16 Mission Therapeutics Ltd Novel compounds
US20230119013A1 (en) 2020-04-08 2023-04-20 Mission Therapeutics Limited N-cyanopyrrolidines with activity as usp30 inhibitors
CA3185027A1 (en) 2020-05-28 2021-12-02 Mission Therapeutics Limited N-(1-cyano-pyrrolidin-3-yl)-5-(3-(trifluoromethyl)phenyl)oxazole-2-carboxamide derivatives and the corresponding oxadiazole derivatives as usp30 inhibitors for the treatment of mi tochondrial dysfunction
JP7796047B2 (en) 2020-06-04 2026-01-08 ミッション セラピューティクス リミティド N-cyanopyrrolidines with activity as USP30 inhibitors
CN115836073B (en) 2020-06-08 2024-08-27 特殊治疗有限公司 1-(5-(2-cyanopyridin-4-yl)oxazole-2-carbonyl)-4-methylhexahydropyrrolo[3,4-B]pyrrole-5(1H)-carbonitrile as USP30 inhibitor for the treatment of mitochondrial dysfunction, cancer and fibrosis
GB202016800D0 (en) 2020-10-22 2020-12-09 Mission Therapeutics Ltd Novel compounds
JP2024544660A (en) 2021-12-01 2024-12-03 ミッション セラピューティクス リミティド Substituted N-cyanopyrrolidines with activity as USP30 inhibitors
GB202408928D0 (en) 2024-06-21 2024-08-07 Mission Therapeutics Ltd Novel compounds
GB202411060D0 (en) 2024-07-29 2024-09-11 Mission Therapeutics Ltd Novel compounds

Citations (191)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001019798A2 (en) 1999-09-17 2001-03-22 Cor Therapeutics Inc. INHIBITORS OF FACTOR Xa
WO2001019788A2 (en) 1999-09-17 2001-03-22 Cor Therapeutics, Inc. BENZAMIDES AND RELATED INHIBITORS OF FACTOR Xa
WO2001029007A1 (en) 1999-10-18 2001-04-26 University Of Connecticut Pyrazole derivatives as cannabinoid receptor antagonists
WO2001064642A2 (en) 2000-02-29 2001-09-07 Cor Therapeutics, Inc. Benzamides and related inhibitors of factor xa
WO2001077073A1 (en) 2000-04-06 2001-10-18 Merck Frosst Canada & Co. Cathepsin cysteine protease inhibitors
WO2002046159A1 (en) 2000-12-06 2002-06-13 Aventis Pharma Deutschland Gmbh Guanidine and amidine derivatives as factor xa inhibitors
WO2002051831A1 (en) 2000-12-23 2002-07-04 Aventis Pharma Deutschland Gmbh Oxybenzamides derivatives as factor xa inhibitors
WO2003007955A2 (en) 2001-07-20 2003-01-30 Cancer Research Technology Limited Biphenyl apurinic/apyrimidinic site endonuclease inhibitors to treat cancer
WO2003020217A2 (en) 2001-08-31 2003-03-13 University Of Connecticut Novel pyrazole analogs acting on cannabinoid receptors
US6576632B1 (en) 1999-08-27 2003-06-10 Pfizer Inc Biaryl compounds useful as anticancer agents
US20030191279A1 (en) 1999-08-27 2003-10-09 Goldstein Steven Wayne Urea derivatives useful as anticancer agents
US6632815B2 (en) 1999-09-17 2003-10-14 Millennium Pharmaceuticals, Inc. Inhibitors of factor Xa
WO2004002481A1 (en) 2002-06-27 2004-01-08 Novo Nordisk A/S Aryl carbonyl derivatives as therapeutic agents
WO2004014370A2 (en) 2002-08-09 2004-02-19 Astrazeneca Ab Oxadiazoles as modulators of metabotropic glutamate receptor-5
WO2004014902A2 (en) 2002-08-09 2004-02-19 Astrazeneca Ab Compounds having an activity at metabotropic glutamate receptors
WO2004080966A1 (en) 2003-03-14 2004-09-23 Ono Pharmaceutical Co., Ltd. Nitrogen-containing heterocyclic derivatives and drugs containing the same as the active ingredient
WO2004085385A2 (en) 2003-03-20 2004-10-07 Schering Corporation Cannabinoid receptor ligands
WO2004110350A2 (en) 2003-05-14 2004-12-23 Torreypines Therapeutics, Inc. Compouds and uses thereof in modulating amyloid beta
WO2005000300A1 (en) 2003-06-27 2005-01-06 Vernalis (Cambridge) Limited Substituted 5-membered ring compounds and their use
WO2005019200A2 (en) 2003-08-14 2005-03-03 Icos Corporation Aryl piperidine derivatives as vla-1 integrin antagonists and uses thereof
WO2005044797A1 (en) 2003-11-06 2005-05-19 Addex Pharmaceuticals Sa Allosteric modulators of metabotropic glutamate receptors
WO2005077368A2 (en) 2004-02-03 2005-08-25 Astrazeneca Ab Treatment of gastro-esophageal reflux disease (gerd)
WO2005077373A2 (en) 2004-02-03 2005-08-25 Astrazeneca Ab Treatment of gastro-esophageal reflux disease (gerd)
WO2005077345A1 (en) 2004-02-03 2005-08-25 Astrazeneca Ab Compounds for the treatment of gastro-esophageal reflux disease
WO2005080379A1 (en) 2004-02-18 2005-09-01 Astrazeneca Ab Triazole compounds and their use as metabotropic glutamate receptor antagonists
WO2005112540A2 (en) 2004-05-21 2005-12-01 Merck Patent Gmbh Liquid crystal compounds, liquid crystal medium and liquid crystal display
WO2005115374A1 (en) 2004-05-29 2005-12-08 7Tm Pharma A/S Crth2 receptor ligands for therapeutic use
WO2005115382A1 (en) 2004-05-29 2005-12-08 7Tm Pharma A/S Crth2 receptor ligands for medicinal uses
WO2006015279A1 (en) 2004-07-28 2006-02-09 Neurogen Corporation Heterocyclic diamine compounds as ligands of the melanin concentrating hormone receptor useful for the treatment of obesity, diabetes, eating and sexual disorders
WO2006014185A1 (en) 2004-02-18 2006-02-09 Astrazeneca Ab Additional heteropolycyclic compounds and their use as metabotropic glutamate receptor antagonists
WO2006024034A1 (en) 2004-08-25 2006-03-02 Targegen, Inc. Heterocyclic compounds and methods of use
WO2006027076A1 (en) 2004-09-06 2006-03-16 Merck Patent Gmbh Polymerisable liquid crystal material
WO2006045350A1 (en) 2004-10-21 2006-05-04 Merck Patent Gmbh Heterocyclic carbonyl compounds
DE102004054666A1 (en) 2004-11-12 2006-05-18 Bayer Cropscience Gmbh New substituted pyrazol-3-carboxamide derivatives useful to combat harmful plants and for growth regulation of plants
WO2006063113A2 (en) 2004-12-07 2006-06-15 Portola Pharmaceuticals, Inc. Ureas as factor xa inhibitors
WO2006074445A2 (en) 2005-01-10 2006-07-13 Alexandros Makriyannis Novel heteropyrrole analogs acting on cannabiniod receptors
WO2006076202A1 (en) 2005-01-10 2006-07-20 Exelixis, Inc. Heterocyclic carboxamide compounds as steroid nuclear receptors ligands
GB2424881A (en) 2005-04-07 2006-10-11 Merck Patent Gmbh 2,7-Di(halophenyl)-9,9-bisalkylfluorene derivatives for liquid crystal compositions & organic electroluminescent display devices
WO2006113261A2 (en) 2005-04-14 2006-10-26 Bristol-Myers Squibb Company Inhibitors of 11-beta hydroxysteroid dehydrogenase type i
WO2006129199A1 (en) 2005-05-18 2006-12-07 Addex Pharma Sa Novel heterocyclic compounds as positive allosteric modulators of metabotropic glutamate receptors
WO2007024744A2 (en) 2005-08-21 2007-03-01 Exelixis, Inc. Heterocyclic carboxamide compounds as steroid nuclear receptor ligands
WO2007061923A2 (en) 2005-11-18 2007-05-31 Takeda San Diego, Inc. Glucokinase activators
WO2007146838A2 (en) 2006-06-09 2007-12-21 Icos Corporation Substituted phenyl acetic acids as dp-2 antagonists
WO2007144202A1 (en) 2006-06-13 2007-12-21 Bayer Schering Pharma Aktiengesellschaft Substituted aminopyrazolopyridines and salts thereof, their preparations and pharmaceutical compositions comprising them
WO2007144204A1 (en) 2006-06-13 2007-12-21 Bayer Schering Pharma Aktiengesellschaft Substituted aminopyrazolopyridines and salts thereof, their preparations and pharmaceutical compositions comprising them
WO2008028553A1 (en) 2006-09-02 2008-03-13 Merck Patent Gmbh Particle beam process for the alignment of reactive mesogens
WO2008035209A2 (en) 2006-05-30 2008-03-27 Methylgene Inc. Inhibitors of protein tyrosine kinase activity
WO2008073670A2 (en) 2006-12-08 2008-06-19 Millennium Pharmaceuticals, Inc. Unit dose formulations and methods of treating thrombosis with an oral factor xa inhibitor
WO2008071456A2 (en) 2006-12-15 2008-06-19 Bayer Schering Pharma Aktiengesellschaft 3-h-pyrazolopyridines and salts thereof, pharmaceutical compositions comprising same, methods of preparing same and uses of same
WO2008079291A2 (en) 2006-12-20 2008-07-03 Amgen Inc. Substituted heterocycles and methods of use
US7425354B2 (en) 2003-11-19 2008-09-16 Chisso Corporation Photopolymerizable liquid crystal composition, its polymer or polymer composition, and optical compensation element
WO2008141976A1 (en) 2007-05-22 2008-11-27 Via Pharmaceuticals, Inc. Diacylglycerol acyltransferase inhibitors
WO2009010156A2 (en) 2007-07-16 2009-01-22 Bayer Cropscience Ag Substituted phenylpropoargyl compounds, methods for the production thereof, and use of same as herbicides and plant growth regulators
WO2009011850A2 (en) 2007-07-16 2009-01-22 Abbott Laboratories Novel therapeutic compounds
WO2009047105A1 (en) 2007-10-10 2009-04-16 Basf Se Sulphonium salt initiators
JP2009108152A (en) 2007-10-29 2009-05-21 Sumitomo Chemical Co Ltd Polymerizable compound and optical film
WO2009078992A1 (en) 2007-12-17 2009-06-25 Amgen Inc. Linear tricyclic compounds as p38 kinase inhibitors
JP2009149754A (en) 2007-12-20 2009-07-09 Sumitomo Chemical Co Ltd Polymerizable compound and optical film obtained by polymerizing the polymerizable compound
WO2009089042A1 (en) 2008-01-09 2009-07-16 Signal Pharmaceuticals, Llc Pyrazole pyrazine amine compounds as kinase inhibitors, compositions thereof and methods of treatment therewith
WO2009129371A1 (en) 2008-04-18 2009-10-22 Glaxo Group Limited Cathepsin c inhibitors
WO2009158571A1 (en) 2008-06-27 2009-12-30 Avila Therapeutics And Uses Thereof Heteroaryl compounds and uses thereof
JP2010066630A (en) 2008-09-12 2010-03-25 Sumitomo Chemical Co Ltd Method for manufacturing optical film, and optical film
US7687504B2 (en) 2004-03-09 2010-03-30 National Health Research Institutes Pyrrolidine compounds
WO2010048149A2 (en) 2008-10-20 2010-04-29 Kalypsys, Inc. Heterocyclic modulators of gpr119 for treatment of disease
WO2010075376A2 (en) 2008-12-23 2010-07-01 Abbott Laboratories Anti-viral compounds
CN101838264A (en) 2009-03-16 2010-09-22 住友化学株式会社 Compound, optical film, and method for producing optical film
US7807691B2 (en) 2005-05-13 2010-10-05 Eli Lilly And Company Substituted N-arylpyrrolidines as selective androgen receptor modulators
JP2011006360A (en) 2009-06-26 2011-01-13 Sumitomo Chemical Co Ltd Compound, optical film and method for producing optical film
JP2011042606A (en) 2009-08-20 2011-03-03 Sumitomo Chemical Co Ltd Compound, optical film and process for producing optical film
WO2011025706A2 (en) 2009-08-26 2011-03-03 Schering Corporation Heterocyclic amide compounds as protein kinase inhibitors
WO2011031934A1 (en) 2009-09-11 2011-03-17 Enanta Pharmaceuticals, Inc. Hepatitis c virus inhibitors
WO2011053825A2 (en) 2009-10-30 2011-05-05 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Compositions and methods for the treatment or prevention of mitochondrial diseases
WO2011103091A1 (en) 2010-02-18 2011-08-25 Transtech Pharma, Inc. Phenyl-heteroaryl derivatives and methods of use thereof
WO2011126903A2 (en) 2010-03-30 2011-10-13 Verseon, Inc. Multisubstituted aromatic compounds as inhibitors of thrombin
KR101077417B1 (en) 2007-06-12 2011-10-26 주식회사 엘지화학 Retardation film and polarizing plate and liquid crystal display comprising the same
WO2011143495A1 (en) 2010-05-13 2011-11-17 Amgen Inc. Heteroaryloxyheterocyclyl compounds as pde10 inhibitors
WO2011161446A1 (en) 2010-06-21 2011-12-29 The University Of Nottingham Compounds for treating proliferative disorders
WO2012016217A1 (en) 2010-07-29 2012-02-02 Rigel Pharmaceuticals, Inc. Ampk-activating heterocyclic compounds and methods for using the same
WO2012078855A1 (en) 2010-12-08 2012-06-14 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Substituted pyrazolopyrimidines as glucocerebrosidase activators
WO2012083048A2 (en) 2010-12-15 2012-06-21 Abbott Laboratories Anti-viral compounds
WO2012083059A1 (en) 2010-12-15 2012-06-21 Abbott Laboratories Anti-viral compounds
JP2012123292A (en) 2010-12-10 2012-06-28 Konica Minolta Advanced Layers Inc Optical film, and polarizing plate and liquid crystal display device using the same
WO2012129562A2 (en) 2011-03-24 2012-09-27 The Scripps Research Institute Compounds and methods for inducing chondrogenesis
WO2012139425A1 (en) 2011-04-13 2012-10-18 Schering Corporation 5-substituted iminothiazines and their mono-and dioxides as bace inhibitors,compositions,and their use
JP5057056B2 (en) 2007-08-03 2012-10-24 Ｊｓｒ株式会社 Liquid crystal aligning agent, method for producing liquid crystal aligning film, polyamic acid, polyimide and diamine compound
WO2012160015A1 (en) 2011-05-23 2012-11-29 Sanofi Process for the preparation of deuterated compounds containing n-alkyl groups
WO2012166951A1 (en) 2011-05-31 2012-12-06 Receptos, Inc. Novel glp-1 receptor stabilizers and modulators
US8329708B2 (en) 2009-08-20 2012-12-11 Korea Institute Of Science And Technology 1,3,6-substituted indole derivatives having inhibitory activity for protein kinase
WO2012177997A1 (en) 2011-06-22 2012-12-27 The General Hospital Corporation Treatment of proteinopathies
WO2012177782A1 (en) 2011-06-20 2012-12-27 Myrexis, Inc. Compounds and therapeutic uses thereof
WO2013046136A1 (en) 2011-09-27 2013-04-04 Novartis Ag 3-pyrimidin-4-yl-oxazolidin-2-ones as inhibitors of mutant idh
WO2013052845A1 (en) 2011-10-05 2013-04-11 The Board Of Trustees Of The Leland Stanford Junior University Pi-kinase inhibitors with broad spectrum anti-infective activity
WO2013086229A1 (en) 2011-12-07 2013-06-13 Amgen Inc. Bicyclic aryl and heteroaryl sodium channel inhibitors
JP5219583B2 (en) 2008-03-31 2013-06-26 住友化学株式会社 Composition, optical film and method for producing the same, optical member and display device
WO2013106678A1 (en) 2012-01-12 2013-07-18 Envivo Pharmaceuticals, Inc. Tetrasubstituted benzenes
WO2013130890A1 (en) 2012-02-29 2013-09-06 Amgen Inc. Heterobicyclic compounds and their use as phosphodiesterase inhibitors
WO2013132991A1 (en) 2012-03-08 2013-09-12 富士フイルム株式会社 Compound, liquid crystal composition, polymer material and film
WO2013178816A1 (en) 2012-06-01 2013-12-05 Nogra Pharma Limited Heterocycles capable of modulating t-cell responses, and methods of using same
WO2013182274A1 (en) 2012-06-05 2013-12-12 Ares Trading S.A. Imidazo-oxadiazole and imidazo-thiadiazole derivatives
WO2013190212A1 (en) 2012-06-22 2013-12-27 Diverchim Method for producing chiral peptides
WO2014000846A1 (en) 2012-06-26 2014-01-03 dedeMERCK PATENT GMBH Method of preparing a birefringent polymer film
JP5443720B2 (en) 2008-09-05 2014-03-19 住友化学株式会社 Composition, optical film and method for producing the same, optical member, and display device
WO2014041111A1 (en) 2012-09-17 2014-03-20 F. Hoffmann-La Roche Ag Usp30 inhibitors and methods of use
WO2014068527A1 (en) 2012-11-02 2014-05-08 Pfizer Inc. Bruton's tyrosine kinase inhibitors
WO2014072261A1 (en) 2012-11-07 2014-05-15 F. Hoffmann-La Roche Ag Triazolo compounds
WO2014108053A1 (en) 2013-01-08 2014-07-17 中国药科大学 Polycyclic substituted pyrazole kinase activity inhibitors and use thereof
CN104045552A (en) 2013-03-13 2014-09-17 上海先声药物研究有限公司 Medicinal compound as neuroprotective agent
WO2014140059A1 (en) 2013-03-15 2014-09-18 F. Hoffmann-La Roche Ag ARYL SULFAMIDE AND SULFAMATE DERIVATIVES AS RORc MODULATORS
WO2014159733A1 (en) 2013-03-14 2014-10-02 Curegenix, Inc. Compounds for treatment of fibrosis diseases
WO2014165232A1 (en) 2013-03-12 2014-10-09 Curegenix, Inc. Compounds for treatment of cancer
JP2014232188A (en) 2013-05-29 2014-12-11 コニカミノルタ株式会社 Cellulose acylate film, circularly polarizing plate and image display device
WO2015003816A2 (en) 2013-07-12 2015-01-15 Helmholtz-Zentrum für Infektionsforschung GmbH Cystobactamides
WO2015011284A2 (en) 2013-07-25 2015-01-29 Fondazione Telethon Inhibitors of fapp2 and uses thereof
WO2015010297A1 (en) 2013-07-25 2015-01-29 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
WO2015048547A2 (en) 2013-09-26 2015-04-02 Rigel Pharmaceuticals, Inc. Methods for using and biomarkers for ampk-activating compounds
WO2015048662A2 (en) 2013-09-30 2015-04-02 X-Rx Discovery, Inc. Substituted nicotinimide inhibitors of btk and their preparation and use in the treatment of cancer, inflammation and autoimmune disease
CN104557862A (en) 2014-12-15 2015-04-29 苏州云轩医药科技有限公司 Heterocyclic compound having Wnt signal channel inhibitory activity
WO2015058832A1 (en) 2013-10-21 2015-04-30 Merck Patent Gmbh Method of preparing a birefringent polymer film
WO2015085238A1 (en) 2013-12-05 2015-06-11 The Regents Of The University Of California, A California Corporation Inhibitors of lpxc
WO2015095104A1 (en) 2013-12-18 2015-06-25 Merck Sharp & Dohme Corp. Iminothiadiazepane dioxide compounds as bace inhibitors, compositions, and their use
WO2015106292A1 (en) 2014-01-13 2015-07-16 Coferon, Inc. Bcr-abl tyrosine-kinase ligands capable of dimerizing in an aqueous solution, and methods of using same
WO2015130790A2 (en) 2014-02-25 2015-09-03 Board Of Regents, University Of Texas System Salts of heterocyclic modulators of hif activity for treatment of disease
WO2015173225A1 (en) 2014-05-13 2015-11-19 F. Hoffmann-La Roche Ag Deuterated heterocyclic compounds and their use as imaging agents
WO2015176625A1 (en) 2014-05-22 2015-11-26 南京明德新药研发股份有限公司 HYDRAZINE COMPOUND AS BLOOD COAGULATION FACTOR Xa INHIBITOR
WO2015189646A1 (en) 2014-06-14 2015-12-17 Mission Therapeutics Limited Methodologies for measuring isopeptidase activity in biological samples in a high throughput manner
WO2015197028A1 (en) 2014-06-28 2015-12-30 Sunshine Lake Pharma Co., Ltd. Compounds as hepatitis c virus (hcv) inhibitors and uses thereof in medicine
WO2016007534A1 (en) 2014-07-07 2016-01-14 Genentech, Inc. Therapeutic compounds and methods of use thereof
WO2016008011A1 (en) 2014-07-16 2016-01-21 Novogen ltd Functionalised and substituted indoles as anti-cancer agents
WO2016019237A2 (en) 2014-07-31 2016-02-04 Pharmacyclics Llc Inhibitors of bruton's tyrosine kinase
WO2016016366A1 (en) 2014-07-31 2016-02-04 Boehringer Ingelheim International Gmbh Substituted dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity
WO2016034262A1 (en) 2014-09-05 2016-03-10 Merck Patent Gmbh Formulations and electronic devices
WO2016040449A1 (en) 2014-09-10 2016-03-17 Raze Therapeutics, Inc. 3-phosphoglycerate dehydrogenase inhibitors and uses thereof
WO2016046530A1 (en) 2014-09-23 2016-03-31 Mission Therapeutics Ltd Novel compounds
JP5899607B2 (en) 2009-03-16 2016-04-06 住友化学株式会社 Compound, optical film and method for producing optical film
WO2016109559A2 (en) 2014-12-29 2016-07-07 The United States Of America As Represented By The Secretary, Department Of Health And Human Services Small molecule inhibitors of lactate dehydrogenase and methods of use thereof
US9393244B2 (en) 2013-03-15 2016-07-19 Georgetown University Increasing parkin activity by administering a deubiquitinating enzyme inhibitor
US20160264548A1 (en) 2013-10-21 2016-09-15 Merck Patent Gmbh Heteroaryl compounds as btk inhibitors and uses thereof
WO2016156816A1 (en) 2015-03-30 2016-10-06 Mission Therapeutics Limited 1-cyano-pyrrolidine compounds as usp30 inhibitors
WO2016172631A2 (en) 2015-04-24 2016-10-27 President And Fellows Of Harvard College Substrate selective inhibitors of insulin-degrading enzyme (ide) and uses thereof
US9511142B2 (en) 2014-06-11 2016-12-06 VenatoRx Pharmaceuticals, Inc. Beta-lactamase inhibitors
WO2017002120A1 (en) 2015-07-02 2017-01-05 Yeda Research And Development Co. Ltd. Selective inhibitors of senescent cells and uses thereof
WO2017010399A1 (en) 2015-07-10 2017-01-19 塩野義製薬株式会社 COMPOUNDS HAVING RORγt INHIBITORY EFFECTS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME
WO2017009650A1 (en) 2015-07-14 2017-01-19 Mission Therapeutics Limited Cyanopyrrolidines as dub inhibitors for the treatment of cancer
WO2017019817A1 (en) 2015-07-29 2017-02-02 Medivation Technologies, Inc. Methods and compositions for targeted therapeutics
WO2017019830A1 (en) 2015-07-29 2017-02-02 Medivation Technologies, Inc. Methods and compositions for targeted therapeutics
WO2017019822A1 (en) 2015-07-29 2017-02-02 Medivation Technologies, Inc. Pellet composition containing repair cells
WO2017040982A1 (en) 2015-09-02 2017-03-09 The Regents Of The University Of California Her3 ligands and uses thereof
WO2017040194A1 (en) 2015-09-04 2017-03-09 Dow Agrosciences Llc Molecules having pesticidal utility, and intermediates, compositions, and processes, related thereto
KR101715090B1 (en) 2013-08-28 2017-03-13 한국화학연구원 Novel compound or pharmaceutically acceptable salt thereof and pharmaceutical composition for prevention or treatment of disease caused by influenza virus infection containing the same as an active ingredient
WO2017066705A1 (en) 2015-10-14 2017-04-20 Aquinnah Pharmaceuticals, Inc. Compounds, compositions and methods of use against stress granules
WO2017093718A1 (en) 2015-11-30 2017-06-08 Mission Therapeutics Limited 1-cyano-pyrrolidine derivatives as inhibitors of usp30.
WO2017100558A1 (en) 2015-12-09 2017-06-15 Research Triangle Institute Improved apelin receptor (apj) agonists and uses thereof
WO2017103614A1 (en) 2015-12-17 2017-06-22 Mission Therapeutics Limited Novel Compounds
WO2017109488A1 (en) 2015-12-23 2017-06-29 Mission Therapeutics Limited Cyanopyrrolidine dervivatives as inhibitors for dubs
CN106986859A (en) 2016-01-20 2017-07-28 广东东阳光药业有限公司 Indole derivatives and application thereof
WO2017141036A1 (en) 2016-02-18 2017-08-24 Mission Therapeutics Limited Novel compounds
WO2017149313A1 (en) 2016-03-04 2017-09-08 Mission Therapeutics Limited Spiro-condensed pyrrolidine derivatives as deubiquitylating enzymes (dub) inhibitors
WO2017158388A1 (en) 2016-03-18 2017-09-21 Mission Therapeutics Limited 2-cyanoisoindoline derivatives for treating cancer
WO2017161028A1 (en) 2016-03-16 2017-09-21 Kura Oncology, Inc. Substituted inhibitors of menin-mll and methods of use
WO2017158381A1 (en) 2016-03-18 2017-09-21 Mission Therapeutics Limited 4,6 dihydropyrrolo [3,4-c] pyrazole-5 (1h)-carbonitrile derivates for trating cancer
WO2017162007A1 (en) 2016-03-24 2017-09-28 北京天诚医药科技有限公司 Aromatic amide derivative and preparation method and medicinal application thereof
WO2017163078A1 (en) 2016-03-24 2017-09-28 Mission Therapeutics Limited 1-cyano-pyrrolidine derivatives as dbu inhibitors
WO2018005591A1 (en) 2016-06-29 2018-01-04 Universite De Montreal Biarylmethyl heterocycles
WO2018010514A1 (en) 2016-07-13 2018-01-18 南京天印健华医药科技有限公司 Heterocyclic compound used as fgfr inhibitor
CN107619384A (en) 2016-07-13 2018-01-23 江苏恒瑞医药股份有限公司 Benzheterocyclic derivatives, its preparation method and its application in medicine
WO2018024188A1 (en) 2016-08-02 2018-02-08 上海迪诺医药科技有限公司 Polycyclic compound, and manufacturing method, pharmaceutical composition, and application thereof
WO2018039896A1 (en) 2016-08-30 2018-03-08 Dow Global Technologies Llc Method of attenuating concentration of acrolein
WO2018060691A1 (en) 2016-09-29 2018-04-05 Mission Therapeutics Limited Cyano-subtituted heterocycles with activity as inhibitors of usp30
WO2018060742A1 (en) 2016-09-30 2018-04-05 Mission Therapeutics Limited Cyanopyrrolidine derivatives with activity as inhibitors of usp30
WO2018060689A1 (en) 2016-09-27 2018-04-05 Mission Therapeutics Limited Cyanopyrrolidine derivatives with activity as inhibitors of usp30
WO2018065768A1 (en) 2016-10-05 2018-04-12 Mission Therapeutics Limited Cyano-substituted heterocycles with activity as inhibitors of usp30
US9997717B2 (en) 2014-12-12 2018-06-12 Idemitsu Kosan Co., Ltd. Organic electroluminescence device and electronic device
WO2018106818A1 (en) 2016-12-07 2018-06-14 Kura Oncology, Inc. Methods of promoting beta cell proliferation
WO2018106820A1 (en) 2016-12-07 2018-06-14 Kura Oncology, Inc. Methods of promoting beta cell proliferation
WO2018134352A1 (en) 2017-01-20 2018-07-26 Leo Pharma A/S Bicyclic amines as novel jak kinase inhibitors
WO2018146116A1 (en) 2017-02-08 2018-08-16 Helmholtz-Zentrum Dresden - Rossendorf E.V. In vivo stable hg-197(m) compounds, method for the production thereof and use thereof in nuclear medical diagnostics and endoradionuclide therapy (theranostics)
US20180228923A1 (en) 2017-02-14 2018-08-16 Colossus Biopharma Consultants Co., Ltd. Fluorescent compounds for imaging of blood vessels and blood flow, and an in vivo screen for pro- and anti-angiogenic agents
WO2018157856A1 (en) 2017-03-03 2018-09-07 江苏豪森药业集团有限公司 Amide derivative inhibitor and preparation method and application thereof
WO2018160891A1 (en) 2017-03-01 2018-09-07 Achillion Pharmaceutical, Inc. Pharmaceutical compounds for treatment of medical disorders
WO2018213150A1 (en) 2017-05-15 2018-11-22 Mitobridge, Inc. Usp30 inhibitors
WO2018220355A1 (en) 2017-05-31 2018-12-06 Mission Therapeutics Limited Sulfonamide-substituted cyanopyrrolidines with activity as dub inhibitors
WO2018234775A1 (en) 2017-06-20 2018-12-27 Mission Therapeutics Limited SUBSTITUTED CYANOPYRROLIDINES HAVING ACTIVITY AS DUB INHIBITORS
WO2019071073A1 (en) 2017-10-06 2019-04-11 Forma Therapeutics, Inc. Inhibiting ubiquitin specific peptidase 30
WO2019171042A1 (en) 2018-03-06 2019-09-12 Mission Therapeutics Limited Cyanopyrrolidines as usp30 inhibitors and fibrosis treatment
WO2019222468A1 (en) 2018-05-17 2019-11-21 Forma Therapeutics, Inc. Fused bicyclic compounds useful as ubiquitin-specific peptidase 30 inhibitors
WO2020036940A1 (en) 2018-08-14 2020-02-20 Amgen Inc. N-cyano-7-azanorbornane derivatives and uses thereof
WO2020072964A1 (en) 2018-10-05 2020-04-09 Forma Therapeutics, Inc. Fused pyrrolines which act as ubiquitin-specific protease 30 (usp30) inhibitors
WO2020212351A1 (en) 2019-04-16 2020-10-22 Mission Therapeutics Limited Substituted cyanopyrrolidines with activity as usp30 inhibitors
WO2020212350A1 (en) 2019-04-16 2020-10-22 Mission Therapeutics Limited Substituted cyanopyrrolidines with activity as usp30 inhibitors
WO2021043870A1 (en) 2019-09-04 2021-03-11 Mission Therapeutics Limited Substituted cyanopyrrolidines with activity as usp30 inhibitors
WO2021050992A1 (en) 2019-09-11 2021-03-18 Vincere Biosciences, Inc. Usp30 inhibitors and uses thereof

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JO3793B1 (en) * 2015-12-10 2021-01-31 Janssen Pharmaceutica Nv Proton tyrosine kinase inhibitors and how to use them

Patent Citations (210)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6576632B1 (en) 1999-08-27 2003-06-10 Pfizer Inc Biaryl compounds useful as anticancer agents
US20030191279A1 (en) 1999-08-27 2003-10-09 Goldstein Steven Wayne Urea derivatives useful as anticancer agents
WO2001019788A2 (en) 1999-09-17 2001-03-22 Cor Therapeutics, Inc. BENZAMIDES AND RELATED INHIBITORS OF FACTOR Xa
WO2001019798A2 (en) 1999-09-17 2001-03-22 Cor Therapeutics Inc. INHIBITORS OF FACTOR Xa
US6632815B2 (en) 1999-09-17 2003-10-14 Millennium Pharmaceuticals, Inc. Inhibitors of factor Xa
WO2001029007A1 (en) 1999-10-18 2001-04-26 University Of Connecticut Pyrazole derivatives as cannabinoid receptor antagonists
WO2001064643A2 (en) 2000-02-29 2001-09-07 Cor Therapeutics, Inc. BENZAMIDES AND RELATED INHIBITORS OF FACTOR Xa
US6376515B2 (en) 2000-02-29 2002-04-23 Cor Therapeutics, Inc. Benzamides and related inhibitors of factor Xa
WO2001064642A2 (en) 2000-02-29 2001-09-07 Cor Therapeutics, Inc. Benzamides and related inhibitors of factor xa
WO2001077073A1 (en) 2000-04-06 2001-10-18 Merck Frosst Canada & Co. Cathepsin cysteine protease inhibitors
US6835727B2 (en) 2000-04-06 2004-12-28 Merck Frosst Canada & Co. Cathepsin cysteine protease inhibitors
WO2002046159A1 (en) 2000-12-06 2002-06-13 Aventis Pharma Deutschland Gmbh Guanidine and amidine derivatives as factor xa inhibitors
WO2002051831A1 (en) 2000-12-23 2002-07-04 Aventis Pharma Deutschland Gmbh Oxybenzamides derivatives as factor xa inhibitors
WO2003007955A2 (en) 2001-07-20 2003-01-30 Cancer Research Technology Limited Biphenyl apurinic/apyrimidinic site endonuclease inhibitors to treat cancer
WO2003020217A2 (en) 2001-08-31 2003-03-13 University Of Connecticut Novel pyrazole analogs acting on cannabinoid receptors
WO2004002481A1 (en) 2002-06-27 2004-01-08 Novo Nordisk A/S Aryl carbonyl derivatives as therapeutic agents
WO2004014902A2 (en) 2002-08-09 2004-02-19 Astrazeneca Ab Compounds having an activity at metabotropic glutamate receptors
WO2004014370A2 (en) 2002-08-09 2004-02-19 Astrazeneca Ab Oxadiazoles as modulators of metabotropic glutamate receptor-5
WO2004080966A1 (en) 2003-03-14 2004-09-23 Ono Pharmaceutical Co., Ltd. Nitrogen-containing heterocyclic derivatives and drugs containing the same as the active ingredient
US7910741B2 (en) 2003-03-14 2011-03-22 Ono Pharmaceutical Co., Ltd. Nitrogen-containing heterocyclic derivatives and drugs containing the same as the active ingredient
WO2004085385A2 (en) 2003-03-20 2004-10-07 Schering Corporation Cannabinoid receptor ligands
WO2004110350A2 (en) 2003-05-14 2004-12-23 Torreypines Therapeutics, Inc. Compouds and uses thereof in modulating amyloid beta
WO2005000300A1 (en) 2003-06-27 2005-01-06 Vernalis (Cambridge) Limited Substituted 5-membered ring compounds and their use
WO2005019200A2 (en) 2003-08-14 2005-03-03 Icos Corporation Aryl piperidine derivatives as vla-1 integrin antagonists and uses thereof
WO2005044797A1 (en) 2003-11-06 2005-05-19 Addex Pharmaceuticals Sa Allosteric modulators of metabotropic glutamate receptors
US7425354B2 (en) 2003-11-19 2008-09-16 Chisso Corporation Photopolymerizable liquid crystal composition, its polymer or polymer composition, and optical compensation element
WO2005077345A1 (en) 2004-02-03 2005-08-25 Astrazeneca Ab Compounds for the treatment of gastro-esophageal reflux disease
WO2005077373A2 (en) 2004-02-03 2005-08-25 Astrazeneca Ab Treatment of gastro-esophageal reflux disease (gerd)
WO2005077368A2 (en) 2004-02-03 2005-08-25 Astrazeneca Ab Treatment of gastro-esophageal reflux disease (gerd)
WO2005080379A1 (en) 2004-02-18 2005-09-01 Astrazeneca Ab Triazole compounds and their use as metabotropic glutamate receptor antagonists
WO2006014185A1 (en) 2004-02-18 2006-02-09 Astrazeneca Ab Additional heteropolycyclic compounds and their use as metabotropic glutamate receptor antagonists
US7687504B2 (en) 2004-03-09 2010-03-30 National Health Research Institutes Pyrrolidine compounds
WO2005112540A2 (en) 2004-05-21 2005-12-01 Merck Patent Gmbh Liquid crystal compounds, liquid crystal medium and liquid crystal display
WO2005115382A1 (en) 2004-05-29 2005-12-08 7Tm Pharma A/S Crth2 receptor ligands for medicinal uses
WO2005115374A1 (en) 2004-05-29 2005-12-08 7Tm Pharma A/S Crth2 receptor ligands for therapeutic use
WO2006015279A1 (en) 2004-07-28 2006-02-09 Neurogen Corporation Heterocyclic diamine compounds as ligands of the melanin concentrating hormone receptor useful for the treatment of obesity, diabetes, eating and sexual disorders
WO2006024034A1 (en) 2004-08-25 2006-03-02 Targegen, Inc. Heterocyclic compounds and methods of use
WO2006027076A1 (en) 2004-09-06 2006-03-16 Merck Patent Gmbh Polymerisable liquid crystal material
WO2006045350A1 (en) 2004-10-21 2006-05-04 Merck Patent Gmbh Heterocyclic carbonyl compounds
US8815924B2 (en) 2004-10-21 2014-08-26 Merck Patent Gmbh Heterocyclic carbonyl compounds
DE102004054666A1 (en) 2004-11-12 2006-05-18 Bayer Cropscience Gmbh New substituted pyrazol-3-carboxamide derivatives useful to combat harmful plants and for growth regulation of plants
WO2006063113A2 (en) 2004-12-07 2006-06-15 Portola Pharmaceuticals, Inc. Ureas as factor xa inhibitors
WO2006076202A1 (en) 2005-01-10 2006-07-20 Exelixis, Inc. Heterocyclic carboxamide compounds as steroid nuclear receptors ligands
WO2006074445A2 (en) 2005-01-10 2006-07-13 Alexandros Makriyannis Novel heteropyrrole analogs acting on cannabiniod receptors
GB2424881A (en) 2005-04-07 2006-10-11 Merck Patent Gmbh 2,7-Di(halophenyl)-9,9-bisalkylfluorene derivatives for liquid crystal compositions & organic electroluminescent display devices
WO2006113261A2 (en) 2005-04-14 2006-10-26 Bristol-Myers Squibb Company Inhibitors of 11-beta hydroxysteroid dehydrogenase type i
US7807691B2 (en) 2005-05-13 2010-10-05 Eli Lilly And Company Substituted N-arylpyrrolidines as selective androgen receptor modulators
WO2006129199A1 (en) 2005-05-18 2006-12-07 Addex Pharma Sa Novel heterocyclic compounds as positive allosteric modulators of metabotropic glutamate receptors
WO2007024744A2 (en) 2005-08-21 2007-03-01 Exelixis, Inc. Heterocyclic carboxamide compounds as steroid nuclear receptor ligands
WO2007061923A2 (en) 2005-11-18 2007-05-31 Takeda San Diego, Inc. Glucokinase activators
WO2008035209A2 (en) 2006-05-30 2008-03-27 Methylgene Inc. Inhibitors of protein tyrosine kinase activity
WO2007146838A2 (en) 2006-06-09 2007-12-21 Icos Corporation Substituted phenyl acetic acids as dp-2 antagonists
WO2007144204A1 (en) 2006-06-13 2007-12-21 Bayer Schering Pharma Aktiengesellschaft Substituted aminopyrazolopyridines and salts thereof, their preparations and pharmaceutical compositions comprising them
WO2007144202A1 (en) 2006-06-13 2007-12-21 Bayer Schering Pharma Aktiengesellschaft Substituted aminopyrazolopyridines and salts thereof, their preparations and pharmaceutical compositions comprising them
WO2008028553A1 (en) 2006-09-02 2008-03-13 Merck Patent Gmbh Particle beam process for the alignment of reactive mesogens
WO2008073670A2 (en) 2006-12-08 2008-06-19 Millennium Pharmaceuticals, Inc. Unit dose formulations and methods of treating thrombosis with an oral factor xa inhibitor
WO2008071456A2 (en) 2006-12-15 2008-06-19 Bayer Schering Pharma Aktiengesellschaft 3-h-pyrazolopyridines and salts thereof, pharmaceutical compositions comprising same, methods of preparing same and uses of same
WO2008079291A2 (en) 2006-12-20 2008-07-03 Amgen Inc. Substituted heterocycles and methods of use
WO2008141976A1 (en) 2007-05-22 2008-11-27 Via Pharmaceuticals, Inc. Diacylglycerol acyltransferase inhibitors
KR101077417B1 (en) 2007-06-12 2011-10-26 주식회사 엘지화학 Retardation film and polarizing plate and liquid crystal display comprising the same
WO2009010156A2 (en) 2007-07-16 2009-01-22 Bayer Cropscience Ag Substituted phenylpropoargyl compounds, methods for the production thereof, and use of same as herbicides and plant growth regulators
WO2009011850A2 (en) 2007-07-16 2009-01-22 Abbott Laboratories Novel therapeutic compounds
JP5057056B2 (en) 2007-08-03 2012-10-24 Ｊｓｒ株式会社 Liquid crystal aligning agent, method for producing liquid crystal aligning film, polyamic acid, polyimide and diamine compound
WO2009047105A1 (en) 2007-10-10 2009-04-16 Basf Se Sulphonium salt initiators
JP2009108152A (en) 2007-10-29 2009-05-21 Sumitomo Chemical Co Ltd Polymerizable compound and optical film
WO2009078992A1 (en) 2007-12-17 2009-06-25 Amgen Inc. Linear tricyclic compounds as p38 kinase inhibitors
JP2009149754A (en) 2007-12-20 2009-07-09 Sumitomo Chemical Co Ltd Polymerizable compound and optical film obtained by polymerizing the polymerizable compound
WO2009089042A1 (en) 2008-01-09 2009-07-16 Signal Pharmaceuticals, Llc Pyrazole pyrazine amine compounds as kinase inhibitors, compositions thereof and methods of treatment therewith
JP5219583B2 (en) 2008-03-31 2013-06-26 住友化学株式会社 Composition, optical film and method for producing the same, optical member and display device
WO2009129371A1 (en) 2008-04-18 2009-10-22 Glaxo Group Limited Cathepsin c inhibitors
US20090264499A1 (en) 2008-04-18 2009-10-22 Jianghe Deng Cathepsin C Inhibitors
WO2009158571A1 (en) 2008-06-27 2009-12-30 Avila Therapeutics And Uses Thereof Heteroaryl compounds and uses thereof
JP5443720B2 (en) 2008-09-05 2014-03-19 住友化学株式会社 Composition, optical film and method for producing the same, optical member, and display device
JP2010066630A (en) 2008-09-12 2010-03-25 Sumitomo Chemical Co Ltd Method for manufacturing optical film, and optical film
WO2010048149A2 (en) 2008-10-20 2010-04-29 Kalypsys, Inc. Heterocyclic modulators of gpr119 for treatment of disease
WO2010075376A2 (en) 2008-12-23 2010-07-01 Abbott Laboratories Anti-viral compounds
CN101838264A (en) 2009-03-16 2010-09-22 住友化学株式会社 Compound, optical film, and method for producing optical film
JP5899607B2 (en) 2009-03-16 2016-04-06 住友化学株式会社 Compound, optical film and method for producing optical film
JP2011006360A (en) 2009-06-26 2011-01-13 Sumitomo Chemical Co Ltd Compound, optical film and method for producing optical film
JP2011042606A (en) 2009-08-20 2011-03-03 Sumitomo Chemical Co Ltd Compound, optical film and process for producing optical film
US8329708B2 (en) 2009-08-20 2012-12-11 Korea Institute Of Science And Technology 1,3,6-substituted indole derivatives having inhibitory activity for protein kinase
WO2011025706A2 (en) 2009-08-26 2011-03-03 Schering Corporation Heterocyclic amide compounds as protein kinase inhibitors
WO2011031934A1 (en) 2009-09-11 2011-03-17 Enanta Pharmaceuticals, Inc. Hepatitis c virus inhibitors
WO2011053825A2 (en) 2009-10-30 2011-05-05 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Compositions and methods for the treatment or prevention of mitochondrial diseases
WO2011103091A1 (en) 2010-02-18 2011-08-25 Transtech Pharma, Inc. Phenyl-heteroaryl derivatives and methods of use thereof
WO2011126903A2 (en) 2010-03-30 2011-10-13 Verseon, Inc. Multisubstituted aromatic compounds as inhibitors of thrombin
WO2011143495A1 (en) 2010-05-13 2011-11-17 Amgen Inc. Heteroaryloxyheterocyclyl compounds as pde10 inhibitors
WO2011161446A1 (en) 2010-06-21 2011-12-29 The University Of Nottingham Compounds for treating proliferative disorders
WO2012016217A1 (en) 2010-07-29 2012-02-02 Rigel Pharmaceuticals, Inc. Ampk-activating heterocyclic compounds and methods for using the same
WO2012078855A1 (en) 2010-12-08 2012-06-14 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Substituted pyrazolopyrimidines as glucocerebrosidase activators
JP2012123292A (en) 2010-12-10 2012-06-28 Konica Minolta Advanced Layers Inc Optical film, and polarizing plate and liquid crystal display device using the same
WO2012083048A2 (en) 2010-12-15 2012-06-21 Abbott Laboratories Anti-viral compounds
WO2012083059A1 (en) 2010-12-15 2012-06-21 Abbott Laboratories Anti-viral compounds
WO2012129562A2 (en) 2011-03-24 2012-09-27 The Scripps Research Institute Compounds and methods for inducing chondrogenesis
WO2012139425A1 (en) 2011-04-13 2012-10-18 Schering Corporation 5-substituted iminothiazines and their mono-and dioxides as bace inhibitors,compositions,and their use
WO2012160015A1 (en) 2011-05-23 2012-11-29 Sanofi Process for the preparation of deuterated compounds containing n-alkyl groups
WO2012166951A1 (en) 2011-05-31 2012-12-06 Receptos, Inc. Novel glp-1 receptor stabilizers and modulators
WO2012177782A1 (en) 2011-06-20 2012-12-27 Myrexis, Inc. Compounds and therapeutic uses thereof
WO2012177997A1 (en) 2011-06-22 2012-12-27 The General Hospital Corporation Treatment of proteinopathies
WO2013046136A1 (en) 2011-09-27 2013-04-04 Novartis Ag 3-pyrimidin-4-yl-oxazolidin-2-ones as inhibitors of mutant idh
WO2013052845A1 (en) 2011-10-05 2013-04-11 The Board Of Trustees Of The Leland Stanford Junior University Pi-kinase inhibitors with broad spectrum anti-infective activity
WO2013086229A1 (en) 2011-12-07 2013-06-13 Amgen Inc. Bicyclic aryl and heteroaryl sodium channel inhibitors
WO2013106678A1 (en) 2012-01-12 2013-07-18 Envivo Pharmaceuticals, Inc. Tetrasubstituted benzenes
WO2013130890A1 (en) 2012-02-29 2013-09-06 Amgen Inc. Heterobicyclic compounds and their use as phosphodiesterase inhibitors
WO2013132991A1 (en) 2012-03-08 2013-09-12 富士フイルム株式会社 Compound, liquid crystal composition, polymer material and film
WO2013178816A1 (en) 2012-06-01 2013-12-05 Nogra Pharma Limited Heterocycles capable of modulating t-cell responses, and methods of using same
WO2013182274A1 (en) 2012-06-05 2013-12-12 Ares Trading S.A. Imidazo-oxadiazole and imidazo-thiadiazole derivatives
WO2013190212A1 (en) 2012-06-22 2013-12-27 Diverchim Method for producing chiral peptides
WO2014000846A1 (en) 2012-06-26 2014-01-03 dedeMERCK PATENT GMBH Method of preparing a birefringent polymer film
WO2014041111A1 (en) 2012-09-17 2014-03-20 F. Hoffmann-La Roche Ag Usp30 inhibitors and methods of use
WO2014068527A1 (en) 2012-11-02 2014-05-08 Pfizer Inc. Bruton's tyrosine kinase inhibitors
WO2014072261A1 (en) 2012-11-07 2014-05-15 F. Hoffmann-La Roche Ag Triazolo compounds
WO2014108053A1 (en) 2013-01-08 2014-07-17 中国药科大学 Polycyclic substituted pyrazole kinase activity inhibitors and use thereof
US9550792B2 (en) 2013-01-08 2017-01-24 Shanghai Fosun Pharmaceutical Development Co., Ltd. Polycyclic substituted pyrazole kinase activity inhibitors and use thereof
WO2014165232A1 (en) 2013-03-12 2014-10-09 Curegenix, Inc. Compounds for treatment of cancer
CN104045552A (en) 2013-03-13 2014-09-17 上海先声药物研究有限公司 Medicinal compound as neuroprotective agent
WO2014159733A1 (en) 2013-03-14 2014-10-02 Curegenix, Inc. Compounds for treatment of fibrosis diseases
US9393244B2 (en) 2013-03-15 2016-07-19 Georgetown University Increasing parkin activity by administering a deubiquitinating enzyme inhibitor
WO2014140059A1 (en) 2013-03-15 2014-09-18 F. Hoffmann-La Roche Ag ARYL SULFAMIDE AND SULFAMATE DERIVATIVES AS RORc MODULATORS
JP2014232188A (en) 2013-05-29 2014-12-11 コニカミノルタ株式会社 Cellulose acylate film, circularly polarizing plate and image display device
WO2015003816A2 (en) 2013-07-12 2015-01-15 Helmholtz-Zentrum für Infektionsforschung GmbH Cystobactamides
WO2015010297A1 (en) 2013-07-25 2015-01-29 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
WO2015011284A2 (en) 2013-07-25 2015-01-29 Fondazione Telethon Inhibitors of fapp2 and uses thereof
KR101715090B1 (en) 2013-08-28 2017-03-13 한국화학연구원 Novel compound or pharmaceutically acceptable salt thereof and pharmaceutical composition for prevention or treatment of disease caused by influenza virus infection containing the same as an active ingredient
WO2015048547A2 (en) 2013-09-26 2015-04-02 Rigel Pharmaceuticals, Inc. Methods for using and biomarkers for ampk-activating compounds
WO2015048662A2 (en) 2013-09-30 2015-04-02 X-Rx Discovery, Inc. Substituted nicotinimide inhibitors of btk and their preparation and use in the treatment of cancer, inflammation and autoimmune disease
WO2015058832A1 (en) 2013-10-21 2015-04-30 Merck Patent Gmbh Method of preparing a birefringent polymer film
US20160264548A1 (en) 2013-10-21 2016-09-15 Merck Patent Gmbh Heteroaryl compounds as btk inhibitors and uses thereof
WO2015085238A1 (en) 2013-12-05 2015-06-11 The Regents Of The University Of California, A California Corporation Inhibitors of lpxc
WO2015095104A1 (en) 2013-12-18 2015-06-25 Merck Sharp & Dohme Corp. Iminothiadiazepane dioxide compounds as bace inhibitors, compositions, and their use
WO2015106292A1 (en) 2014-01-13 2015-07-16 Coferon, Inc. Bcr-abl tyrosine-kinase ligands capable of dimerizing in an aqueous solution, and methods of using same
WO2015130790A2 (en) 2014-02-25 2015-09-03 Board Of Regents, University Of Texas System Salts of heterocyclic modulators of hif activity for treatment of disease
WO2015173225A1 (en) 2014-05-13 2015-11-19 F. Hoffmann-La Roche Ag Deuterated heterocyclic compounds and their use as imaging agents
WO2015176625A1 (en) 2014-05-22 2015-11-26 南京明德新药研发股份有限公司 HYDRAZINE COMPOUND AS BLOOD COAGULATION FACTOR Xa INHIBITOR
US9938272B2 (en) 2014-05-22 2018-04-10 North China Pharmaceutical Company., Ltd. Hydrazine compound as blood coagulation factor Xa inhibitor
US9511142B2 (en) 2014-06-11 2016-12-06 VenatoRx Pharmaceuticals, Inc. Beta-lactamase inhibitors
WO2015189646A1 (en) 2014-06-14 2015-12-17 Mission Therapeutics Limited Methodologies for measuring isopeptidase activity in biological samples in a high throughput manner
WO2015197028A1 (en) 2014-06-28 2015-12-30 Sunshine Lake Pharma Co., Ltd. Compounds as hepatitis c virus (hcv) inhibitors and uses thereof in medicine
WO2016007534A1 (en) 2014-07-07 2016-01-14 Genentech, Inc. Therapeutic compounds and methods of use thereof
WO2016008011A1 (en) 2014-07-16 2016-01-21 Novogen ltd Functionalised and substituted indoles as anti-cancer agents
WO2016019237A2 (en) 2014-07-31 2016-02-04 Pharmacyclics Llc Inhibitors of bruton's tyrosine kinase
WO2016016366A1 (en) 2014-07-31 2016-02-04 Boehringer Ingelheim International Gmbh Substituted dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity
WO2016034262A1 (en) 2014-09-05 2016-03-10 Merck Patent Gmbh Formulations and electronic devices
US10615343B2 (en) 2014-09-05 2020-04-07 Merck Patent Gmbh Formulations and electronic devices
WO2016040449A1 (en) 2014-09-10 2016-03-17 Raze Therapeutics, Inc. 3-phosphoglycerate dehydrogenase inhibitors and uses thereof
US20170247365A1 (en) 2014-09-23 2017-08-31 Mission Therapeutics Ltd Novel compounds
WO2016046530A1 (en) 2014-09-23 2016-03-31 Mission Therapeutics Ltd Novel compounds
US9926307B2 (en) 2014-09-23 2018-03-27 Mission Therapeutics Ltd Compounds
US9997717B2 (en) 2014-12-12 2018-06-12 Idemitsu Kosan Co., Ltd. Organic electroluminescence device and electronic device
CN104557862A (en) 2014-12-15 2015-04-29 苏州云轩医药科技有限公司 Heterocyclic compound having Wnt signal channel inhibitory activity
WO2016109559A2 (en) 2014-12-29 2016-07-07 The United States Of America As Represented By The Secretary, Department Of Health And Human Services Small molecule inhibitors of lactate dehydrogenase and methods of use thereof
WO2016156816A1 (en) 2015-03-30 2016-10-06 Mission Therapeutics Limited 1-cyano-pyrrolidine compounds as usp30 inhibitors
WO2016172631A2 (en) 2015-04-24 2016-10-27 President And Fellows Of Harvard College Substrate selective inhibitors of insulin-degrading enzyme (ide) and uses thereof
WO2017002120A1 (en) 2015-07-02 2017-01-05 Yeda Research And Development Co. Ltd. Selective inhibitors of senescent cells and uses thereof
WO2017010399A1 (en) 2015-07-10 2017-01-19 塩野義製薬株式会社 COMPOUNDS HAVING RORγt INHIBITORY EFFECTS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME
WO2017009650A1 (en) 2015-07-14 2017-01-19 Mission Therapeutics Limited Cyanopyrrolidines as dub inhibitors for the treatment of cancer
WO2017019830A1 (en) 2015-07-29 2017-02-02 Medivation Technologies, Inc. Methods and compositions for targeted therapeutics
WO2017019822A1 (en) 2015-07-29 2017-02-02 Medivation Technologies, Inc. Pellet composition containing repair cells
WO2017019817A1 (en) 2015-07-29 2017-02-02 Medivation Technologies, Inc. Methods and compositions for targeted therapeutics
WO2017040982A1 (en) 2015-09-02 2017-03-09 The Regents Of The University Of California Her3 ligands and uses thereof
WO2017040194A1 (en) 2015-09-04 2017-03-09 Dow Agrosciences Llc Molecules having pesticidal utility, and intermediates, compositions, and processes, related thereto
WO2017066705A1 (en) 2015-10-14 2017-04-20 Aquinnah Pharmaceuticals, Inc. Compounds, compositions and methods of use against stress granules
WO2017093718A1 (en) 2015-11-30 2017-06-08 Mission Therapeutics Limited 1-cyano-pyrrolidine derivatives as inhibitors of usp30.
WO2017100558A1 (en) 2015-12-09 2017-06-15 Research Triangle Institute Improved apelin receptor (apj) agonists and uses thereof
WO2017103614A1 (en) 2015-12-17 2017-06-22 Mission Therapeutics Limited Novel Compounds
WO2017109488A1 (en) 2015-12-23 2017-06-29 Mission Therapeutics Limited Cyanopyrrolidine dervivatives as inhibitors for dubs
CN106986859A (en) 2016-01-20 2017-07-28 广东东阳光药业有限公司 Indole derivatives and application thereof
WO2017141036A1 (en) 2016-02-18 2017-08-24 Mission Therapeutics Limited Novel compounds
WO2017149313A1 (en) 2016-03-04 2017-09-08 Mission Therapeutics Limited Spiro-condensed pyrrolidine derivatives as deubiquitylating enzymes (dub) inhibitors
WO2017161028A1 (en) 2016-03-16 2017-09-21 Kura Oncology, Inc. Substituted inhibitors of menin-mll and methods of use
WO2017158388A1 (en) 2016-03-18 2017-09-21 Mission Therapeutics Limited 2-cyanoisoindoline derivatives for treating cancer
WO2017158381A1 (en) 2016-03-18 2017-09-21 Mission Therapeutics Limited 4,6 dihydropyrrolo [3,4-c] pyrazole-5 (1h)-carbonitrile derivates for trating cancer
WO2017162007A1 (en) 2016-03-24 2017-09-28 北京天诚医药科技有限公司 Aromatic amide derivative and preparation method and medicinal application thereof
WO2017163078A1 (en) 2016-03-24 2017-09-28 Mission Therapeutics Limited 1-cyano-pyrrolidine derivatives as dbu inhibitors
WO2018005591A1 (en) 2016-06-29 2018-01-04 Universite De Montreal Biarylmethyl heterocycles
US10590109B2 (en) 2016-07-13 2020-03-17 Nanjing Innocare Pharma Tech Co., Ltd. Heterocyclic compounds used as FGFR inhibitors
CN107619384A (en) 2016-07-13 2018-01-23 江苏恒瑞医药股份有限公司 Benzheterocyclic derivatives, its preparation method and its application in medicine
WO2018010514A1 (en) 2016-07-13 2018-01-18 南京天印健华医药科技有限公司 Heterocyclic compound used as fgfr inhibitor
WO2018024188A1 (en) 2016-08-02 2018-02-08 上海迪诺医药科技有限公司 Polycyclic compound, and manufacturing method, pharmaceutical composition, and application thereof
WO2018039896A1 (en) 2016-08-30 2018-03-08 Dow Global Technologies Llc Method of attenuating concentration of acrolein
WO2018060689A1 (en) 2016-09-27 2018-04-05 Mission Therapeutics Limited Cyanopyrrolidine derivatives with activity as inhibitors of usp30
WO2018060691A1 (en) 2016-09-29 2018-04-05 Mission Therapeutics Limited Cyano-subtituted heterocycles with activity as inhibitors of usp30
WO2018060742A1 (en) 2016-09-30 2018-04-05 Mission Therapeutics Limited Cyanopyrrolidine derivatives with activity as inhibitors of usp30
WO2018065768A1 (en) 2016-10-05 2018-04-12 Mission Therapeutics Limited Cyano-substituted heterocycles with activity as inhibitors of usp30
WO2018106818A1 (en) 2016-12-07 2018-06-14 Kura Oncology, Inc. Methods of promoting beta cell proliferation
WO2018106820A1 (en) 2016-12-07 2018-06-14 Kura Oncology, Inc. Methods of promoting beta cell proliferation
WO2018134352A1 (en) 2017-01-20 2018-07-26 Leo Pharma A/S Bicyclic amines as novel jak kinase inhibitors
WO2018146116A1 (en) 2017-02-08 2018-08-16 Helmholtz-Zentrum Dresden - Rossendorf E.V. In vivo stable hg-197(m) compounds, method for the production thereof and use thereof in nuclear medical diagnostics and endoradionuclide therapy (theranostics)
US20180228923A1 (en) 2017-02-14 2018-08-16 Colossus Biopharma Consultants Co., Ltd. Fluorescent compounds for imaging of blood vessels and blood flow, and an in vivo screen for pro- and anti-angiogenic agents
WO2018160891A1 (en) 2017-03-01 2018-09-07 Achillion Pharmaceutical, Inc. Pharmaceutical compounds for treatment of medical disorders
WO2018157856A1 (en) 2017-03-03 2018-09-07 江苏豪森药业集团有限公司 Amide derivative inhibitor and preparation method and application thereof
EP3590931A1 (en) 2017-03-03 2020-01-08 Jiangsu Hansoh Pharmaceutical Group Co., Ltd. Amide derivative inhibitor and preparation method and application thereof
WO2018213150A1 (en) 2017-05-15 2018-11-22 Mitobridge, Inc. Usp30 inhibitors
WO2018220355A1 (en) 2017-05-31 2018-12-06 Mission Therapeutics Limited Sulfonamide-substituted cyanopyrrolidines with activity as dub inhibitors
WO2018234775A1 (en) 2017-06-20 2018-12-27 Mission Therapeutics Limited SUBSTITUTED CYANOPYRROLIDINES HAVING ACTIVITY AS DUB INHIBITORS
WO2019071073A1 (en) 2017-10-06 2019-04-11 Forma Therapeutics, Inc. Inhibiting ubiquitin specific peptidase 30
US20200317658A1 (en) 2017-10-06 2020-10-08 Forma Therapeutics, Inc. Inhibiting ubiquitin specific peptidase 30
US20220185806A1 (en) 2017-10-06 2022-06-16 Forma Therapeutics, Inc. Inhibiting ubiquitin specific peptidase 30
US11247987B2 (en) 2017-10-06 2022-02-15 Forma Therapeutics, Inc. Inhibiting ubiquitin specific peptidase 30
WO2019171042A1 (en) 2018-03-06 2019-09-12 Mission Therapeutics Limited Cyanopyrrolidines as usp30 inhibitors and fibrosis treatment
US20210198263A1 (en) 2018-05-17 2021-07-01 Forma Therapeutics, Inc. Fused bicyclic compounds useful as ubiquitin-specific peptidase 30 inhibitors
WO2019222468A1 (en) 2018-05-17 2019-11-21 Forma Therapeutics, Inc. Fused bicyclic compounds useful as ubiquitin-specific peptidase 30 inhibitors
WO2020036940A1 (en) 2018-08-14 2020-02-20 Amgen Inc. N-cyano-7-azanorbornane derivatives and uses thereof
WO2020072964A1 (en) 2018-10-05 2020-04-09 Forma Therapeutics, Inc. Fused pyrrolines which act as ubiquitin-specific protease 30 (usp30) inhibitors
US20210355126A1 (en) 2018-10-05 2021-11-18 Forma Therapeutics, Inc. Fused pyrrolines which act as ubiquitin-specific protease 30 (usp30) inhibitors
US11535618B2 (en) 2018-10-05 2022-12-27 Forma Therapeutics, Inc. Fused pyrrolines which act as ubiquitin-specific protease 30 (USP30) inhibitors
WO2020212350A1 (en) 2019-04-16 2020-10-22 Mission Therapeutics Limited Substituted cyanopyrrolidines with activity as usp30 inhibitors
WO2020212351A1 (en) 2019-04-16 2020-10-22 Mission Therapeutics Limited Substituted cyanopyrrolidines with activity as usp30 inhibitors
WO2021043870A1 (en) 2019-09-04 2021-03-11 Mission Therapeutics Limited Substituted cyanopyrrolidines with activity as usp30 inhibitors
WO2021050992A1 (en) 2019-09-11 2021-03-18 Vincere Biosciences, Inc. Usp30 inhibitors and uses thereof

Non-Patent Citations (29)

* Cited by examiner, † Cited by third party
Title
Ahmed, H.E.A. and Bajorath, J., Methods for Computer-Aided Chemical Biology, Part 5: Rationalizing the Selectivity of Cathepsin Inhibitors on the Basis of Molecular Fragments and Topological Feature Distributions, Chemical Biology & Drug Design, (74): 129-141 (2009).
Bingol, B. et al., The mitochondrial deubiquitinase USP30 opposes parkin—mediated mitophagy, Nature, 510:370-375 (2014).
Buus, R. et al., Deubiquitinase Activities Required for Hepatocyte Growth Factor-Induced Scattering of Epithelial Cells, Current Bio., 19:1463-1466 (2009).
Deaton, D. N. et al., Novel and potent cyclic cyanamide-based cathepsin K inhibitors, Bioorg. Med. Chem. Lett., 15:1815-1819 (2005).
Dovlatyan, M. et al., A High-Content Live Imaging Mitophagy Assay to Evaluate Small Molecule Mitophagy Enhancers, Poster Abstract (Board No. B555) presented at ASCB EMBO (Dec. 2017).
Durcan, T. M. and Edward, A. F., The three ‘P’s of mitophagy: PARKIN, PINK1, and post-translational modifications, Genes and Development, 29:989-999 (2015).
International Search Report for PCT/US2018/054520, 4 pages (dated Feb. 5, 2019).
International Search Report for PCT/US2019/032619, 5 pages (dated Jul. 16, 2019).
International Search Report for PCT/US2019/054803, 6 pages (dated Nov. 27, 2019).
Iwashita, H. et al., Live Cell Imaging of Mitochondrial Autophagy with a Novel Fluorescent Small Molecule, ACS Chem. Biol., 12:2546-2551 (2017).
Ji, Y. et al., Innate C-H Trifluoromethylation of Heterocycles, PNAS, 108(35):14411-14415 (2011).
Kluge, A. F. et al., Novel Highly Selective Inhibitors of Ubiquitin Specific Protease 30 (USP30) Accelerate Mitophagy, Bioorg. and Medic. Chem. Lett., 28(15):2655-2659 (2018).
Lainé, D., et al., Discovery of Novel Cyanamide-Based Inhibitors of Cathepsin C, ACS Med. Chem. Lett., 2:142-147 (2011).
McWilliams, T. G. et al., mit-QC illuminates mitophagy and mitochondrial architecture in vivo, J. Cell Biol., 214:333-345 (2016).
Nakamura, N. and Hirose, S., Regulation of Mitochondrial Morphology by USP30, a Deubiquitinating Enzyme Present in the Mitochondrial Outer Membrane, Mole. Bio. Cell., 19:1903-1911 (2008).
Ndubaku, C. and Tsui, V., Inhibiting the Deubiquitinating Enzymes (DUBs), Jrnl. Med. Chem., 58:1581-1595 (2015).
Pollock, S.R., and Kashatus, D.F., A novel role for RaIA during PINK1-Parkin mitophagy, Poster Abstract (Board No. B3252) presented at ASCB EMBO (Dec. 2017).
PubChem CID 116045277, (3-Methylcyclobutyl)cyanamide, 2 pages, Date Created: Jan. 30, 2016, Date Modified: Aug. 8, 2020.
PubChem CID 116214356, (1-Ethylcyclobutyl)cyanamide, 2 pages, Date Created: Jan. 30, 2016, Date Modified: Aug. 8, 2020.
PubChem CID 21516572, (1-Methylcyclopropyl)cyanamide, 7 pages, Date Created: Dec. 5, 2007, Date Modified: Apr. 18, 2020.
Puri, R. et al., Mitochondrial Ubiquitin Ligase Mull Mediates an Early Stress Protection of Neuronal Mitochondria From Degradation by Parkin-Mediated Mitophagy, Poster Abstract (Board No. B482) presented at ASCB EMBO (Dec. 2017).
Rusilowicz-Jones, E. et al., A novel USP30 inhibitor recapitulates genetic loss of USP30 and sets the trigger for PINK1-PARKIN amplicfication of mitochondrial ubiquitylation, bioRxiv, doi: https://doi.org/10.1101/2020.04.16.044206, 1-35 (posted Apr. 20, 2020).
Rusilowicz-Jones, E. et al., USP30 sets a trigger threshold for PINK1-PARKIN amplification of mitochondrial ubiquitylation, Life Sci. Alli., 3(8):1-14 (2020).
Rusilowicz-Jones, E. V. et al., Benchmarking a highly selective USP30 inhibitor for enhancement of mitophagy and pexophagy, bioRxiv, doi:https://doi.org/10.1101/2021.04.28.441730, 1-19 (posted Apr. 28, 2021).
Sathe, M. et al., Efficient synthesis of N-cyano αand β-amino esters, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 38: 1375-1380 (2008).
Seiberlich, V. et al., The small molecule inhibitor PR-619 of deubiquitinating enzymes affects the microtubule network and causes protein aggregate formation in neural cells: Implications for neurodegenerative diseases, Biochem Biophys Acta., 1823 (11):2057-2068 (2012).
Silverman, R., "The Organic Chemistry of Drug Design and Drug Action", NY Elsevier, 29-32 (2004).
STN Search Record, 27 pages, (2017).
Thompson, J. E. et al., Discovery of MF-0094, a potent, selective and cell permeable inhibitor of USP30, Poster (2017).

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12049466B2 (en) 2018-05-17 2024-07-30 Forma Therapeutics, Inc. Fused bicyclic compounds useful as ubiquitin-specific peptidase 30 inhibitors

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